Bibliografias temáticas / Intratumoral CD8 T cells

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Literatura científica selecionada sobre o tema "Intratumoral CD8 T cells"

Autor: Grafiati

Publicado: 1 de fevereiro de 2025

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Artigos de revistas sobre o assunto "Intratumoral CD8 T cells"

De Logu, Francesco, Francesca Galli, Romina Nassini, Filippo Ugolini, Sara Simi, Mara Cossa, Clelia Miracco et al. "Digital Immunophenotyping Predicts Disease Free and Overall Survival in Early Stage Melanoma Patients". Cells 10, n.º 2 (17 de fevereiro de 2021): 422. http://dx.doi.org/10.3390/cells10020422.

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Background: the prognostic significance of tumor infiltrating lymphocytes (TILs) in intermediate/thick primary cutaneous melanoma (PCM) remains controversial, partially because conventional evaluation is not reliable, due to inter-observer variability and diverse scoring methods. We aimed to assess the prognostic impact of the density and spatial distribution of immune cells in early stage intermediate/thick PCM. Materials and Methods: digital image acquisition and quantitative analysis of tissue immune biomarkers (CD3, CD4, CD8, CD68, PD-L1, CD163, FOX-P3, and PD-1) was carried out in a training cohort, which included patients with primary PCM ≥ 2 mm diagnosed, treated, and followed-up prospectively in three Italian centers. Results were validated in an independent Italian cohort. Results: in the training cohort, 100 Stage II–III melanoma patients were valuable. At multivariable analysis, a longer disease free survival (DFS) was statistically associated with higher levels of CD4+ intratumoral T-cells (aHR [100 cell/mm2 increase] 0.98, 95%CI 0.95–1.00, p = 0.041) and CD163+ inner peritumoral (aHR [high vs. low] 0.56, 95%CI 0.32–0.99, p = 0.047). A statistically significant longer DFS (aHR [high-high vs. low-low] 0.52, 95%CI 0.28–0.99, p = 0.047) and overall survival (OS) (aHR [high-high vs. low-low] 0.39, 95%CI 0.18–0.85, p = 0.018) was found in patients with a high density of both intratumoral CD8+ T-cells and CD68+ macrophages as compared to those with low density of both intratumoral CD8+ T-cells and CD68+ macrophages. Consistently, in the validation cohort, patients with high density of both intratumoral CD8+ and CD3+ T-cells were associated to a statistically better DFS (aHR[high-high vs. low-low] 0.24, 95%CI 0.10–0.56, p < 0.001) and those with high density of both intratumoral CD8+ and CD68+ were associated to a statistically longer OS (aHR[high-high vs. low-low] 0.28, 95%CI 0.09–0.86, p = 0.025). Conclusion: our findings suggest that a specific preexisting profile of T cells and macrophages distribution in melanomas may predict the risk of recurrence and death with potential implications for the stratification of stage II–III melanoma patients.

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Yang, Zhi-Zhang, Anne J. Novak, Mary J. Stenson, Thomas E. Witzig e Stephen M. Ansell. "Intratumoral Treg Cells Completely Inhibit the Induction and Function of Tumor-Infiltrating CD8+ T-Cells in B-Cell NHL." Blood 106, n.º 11 (16 de novembro de 2005): 3311. http://dx.doi.org/10.1182/blood.v106.11.3311.3311.

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Abstract Background: Numerous studies have shown that lymphoma B-cells are resistant to CTL-mediated death, however the underlying mechanism for this resistance is not clear. In previous work, we have identified a subset of CD4+CD25+ T-cells overrepresented in the tumor sites of B-cell NHL that display a phenotype compatible with regulatory T cells (Treg cells). These cells express high levels of Foxp3 and CTLA-4, and are capable of suppressing the proliferation and cytokine production of autologous infiltrating CD4+CD25- T cells in B-cell NHL. Goal: To explore whether Treg cells exert a suppressive effect on the induction and function of autologous tumor-infiltrating CD8+ T-cells in B-cell NHL. Results: Using fresh specimens obtained from patients with B-cell lymphoma, we found that intratumoral Treg cells had a significantly suppressive effect on autologous tumor-infiltrating CD8+ T-cells in B-cell NHL. When activated CD8+ T-cells were cocultured with infiltrating CD4+CD25- T-cells, they displayed less proliferation than CD8+ T-cells cultured alone. However, we found that with a 1:4 ratio of stimulating cells (Treg cells) to responding cells (CD8+ T-cells), intratumoral Treg cells completely inhibited the proliferation of autologous tumor-infiltrating CD8+ T-cells activated with PHA. Furthermore, we have observed that 20% of infiltrating CD8+ T-cells in fresh isolated samples from B-cell NHL coexpress perforin and granzyme B. When intratumoral Treg cells were cocultured with CD8+ T-cells, the Treg cells inhibited the activation-induced production of perforin and granzyme B of autologous tumor-infiltrating CD8+ T-cells in a dose-dependent fashion. We also found that cytokine treatment (IL-2 and IL-12) or PHA activation induced the capability of tumor-infiltrating CD8+ T-cells to kill lymphoma B-cells, which was accompanied by upregulation of expression of CD107a on the surface of cytotoxic CD8+ T-cells. Intratumoral Treg cells significantly inhibit cytotoxicity of activated infiltrating CD8+ T-cells to lymphoma B-cells. Finally, we found that there was an inverse correlation of cell frequencies between intratumoral Treg cells and tumor-infiltrating CD8+ T cells in patients with B-cell NHL, suggesting that Treg cells may inhibit the migration of cytotoxic T-cells to the sites of B-cell lymphoma. Conclusion: Intratumoral Treg cells dramatically suppress the proliferation and activation-induced production of granules in infiltrating CD8+ T-cells in B-cell NHL. These Treg cells also inhibit the ability of activated tumor-infiltrating CD8+ T-cells to kill lymphoma B-cells in vitro, and may prevent the migration of CD8+ cells to the sites of lymphoma. Taken together, these data indicate an important role for intratumoral Treg cells in CTL-mediated anti-tumor immunity in B-cell NHL.

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Wang, Li-Xin, Suyu Shu, Mary L. Disis e Gregory E. Plautz. "Adoptive transfer of tumor-primed, in vitro–activated, CD4+ T effector cells (TEs) combined with CD8+ TEs provides intratumoral TE proliferation and synergistic antitumor response". Blood 109, n.º 11 (1 de junho de 2007): 4865–76. http://dx.doi.org/10.1182/blood-2006-09-045245.

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Abstract The importance of CD4+ Th1 cells during the effector phase of the antitumor response has been overshadowed by emphasis on CD8+ cytotoxic T lymphocytes (CTLs). To determine their respective functions, we purified antigen-primed T cells from tumor-draining lymph nodes and separately activated CD4+ and CD8+ subsets in vitro. Adoptive transfer of CD4+ T effector cells (TEs) combined with CD8+ TEs provided synergistic therapy for mice bearing subcutaneous, intracranial, or advanced pulmonary metastases. CD4+ TEs augmented IFN-γ production by CD8+ TEs when cells were stimulated by tumor digest–containing antigen-presenting cells (APCs). CD4+ TEs infiltrated and proliferated extensively in pulmonary tumors, while also stimulating tumor antigen–specific CD8+ T cells. By contrast, CD8+ TEs showed minimal intratumoral proliferation in the absence of CD4+ cells or when systemically transferred CD4+ cells were prevented from infiltrating pulmonary tumors by pretreatment with pertussis toxin. Irradiation of CD4+ T cells immediately prior to adoptive transfer abrogated their intratumoral proliferation and direct antitumor efficacy but did not block their capacity to stimulate intratumoral CD8+ TE proliferation or tumor regression. These results highlight the importance of cross-presentation of tumor antigens during the effector phase of immunotherapy and suggest that approaches to stimulate CD4+ TE function and boost APC cross-presentation within tumors will augment cancer immunotherapy.

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Yang, Zhi-Zhang, Anne J. Novak, Steven C. Ziesmer, Thomas E. Witzig e Stephen M. Ansell. "CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25− T cells". Blood 110, n.º 7 (1 de outubro de 2007): 2537–44. http://dx.doi.org/10.1182/blood-2007-03-082578.

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Foxp3 expression was initially thought to be restricted to the CD4+CD25+ regulatory T-cell population. However, recent studies suggest that forkhead box P3 (Foxp3) is expressed in CD4+CD25− T cells in aged mice. In the present study in B-cell non-Hodgkin lymphoma (NHL), we found that a subset of intratumoral but not peripheral blood CD4+CD25− T cells, comprising about 15% of intratumoral CD4+ T cells, express Foxp3 and are capable of suppressing the proliferation of autologous infiltrating CD8+ T cells. In vitro activation with OKT3/anti-CD28 antibody (Ab) or dendritic cells (DCs) induced Foxp3 expression in a subset of these CD4+CD25−Foxp3− T cells. We found that the presence of lymphoma B cells during activation augmented activation-induced Foxp3 expression in CD4+CD25− T cells. We also found that CD70+ lymphoma B cells significantly contributed to the activation-induced Foxp3 expression in intratumoral CD4+CD25− T cells. Furthermore, the blockade of CD27-CD70 interaction by anti-CD70 Ab abrogated lymphoma B-cell–mediated induction of Foxp3 expression in intratumoral CD4+CD25− T cells. Taken together, these studies reveal a novel role for NHL B cells in the development of intratumoral regulatory T cells.

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Fenoglio, Daniela, Liliana Belgioia, Alessia Parodi, Francesco Missale, Almalina Bacigalupo, Alison Tarke, Fabiola Incandela et al. "Development of Exhaustion and Acquisition of Regulatory Function by Infiltrating CD8+CD28− T Lymphocytes Dictate Clinical Outcome in Head and Neck Cancer". Cancers 13, n.º 9 (6 de maio de 2021): 2234. http://dx.doi.org/10.3390/cancers13092234.

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Head and neck squamous cell carcinoma (HNSCC) has a poor clinical outcome despite the presence of a rich CD8+ T cell tumor infiltrate in the majority of patients. This may be due to alterations of tumor infiltrating CD8+ T cells. Here, we performed a characterization of HNSCC infiltrating CD8+ T cells in a cohort of 30 patients. The results showed that differential intratumoral frequency of CD8+CD28+ T cells, CD8+CD28− T cells, and CD8+CD28−CD127−CD39+ Treg distinguished between HNSCC patients who did or did not respond to treatment. Moreover, high PD1 expression identified a CD8+CD28− T cell subpopulation, phenotypically/functionally corresponding to CD8+CD28−CD127−CD39+ Treg, which showed a high expression of markers of exhaustion. This observation suggests that development of exhaustion and acquisition of regulatory properties may configure the late differentiation stage for intratumoral effector T cells, a phenomenon we define as effector-to-regulatory T cell transition.

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Yang, Jing, Jing Han, Zhen Jiang, Chennan Wang, Xin Chen, Rongqing Li, Na Sun, Xiangye Liu, Kuiyang Zheng e Takayuki Ikezoe. "Inhibition of Aurora-A recruited CD8+ T cells infiltration via mediating IL-10 production of cancer cells". Journal of Immunology 204, n.º 1_Supplement (1 de maio de 2020): 241.13. http://dx.doi.org/10.4049/jimmunol.204.supp.241.13.

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Abstract It has been shown that approximately 10% of infiltrated CD8+ T cells could be the tumor-specific intratumoral CD8+ T cells in colorectal cancer. While, inhibition of Aurora-A, a member of serine/threonine Aurora kinase family, by alisertib promoted the percentage of infiltrated intratumoral CD8+ T cells. We therefore assumed that targeting Aurora-A could be a therapeutic strategy for recruitment of intratumoral CD8+ T cells. In CT-26 tumor model, blockade of Aurora-A with alisertib slowed the tumor growth in association with an increased infiltration, activation and expansion of intratumoral CD8+ T cells. We further analyzed the role of Aurora-A in colon cancer associated to colitis using the azoxymethane/dextran sodium sulphate (AOM/DSS) colitis-associated colon cancer model, and found that AURKA deficiency significantly decreased tumor formation, in parallel with an increase in infiltration of intratumoral CD8+ T cells. Gene expression profiling indicated that Il10ra expression was obviously increased in intratumoral CD8+ T cells sorted from alisertib-treated tumors. Antibody-mediated blockade of IL-10Ra dramatically attenuated the anti-tumor ability of alisertib in association with reducing the percentage of intratumoral CD8+ T cells. IL-10Ra was the key mediator of IL-10. We herein examined the levels of IL-10 and found that the levels of IL-10 in the serum of AURKA deficiency mice treated with AOM/DSS were elevated. Additionally, IL-10 obviously promoted migration of CD8+ T cells in vitro. Blockade of Aurora-A increased the transcriptional levels of IL-10. In conclusion, inhibition of Aurora-A could be useful for recruiting infiltration of intratumoral CD8+ T cell by mediating IL-10 production.

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Dorta-Estremera, Stephanie, Krishna Nookala Sita Mahalakshmi, Ananta V. Yanamandra, Lauren Elizabeth Colbert, Guojun Yang, Patricia J. Eifel, Anuja Jhingran et al. "Kinetics of intratumoral T-cell activation during chemoradiation for cervical cancer." Journal of Clinical Oncology 36, n.º 5_suppl (10 de fevereiro de 2018): 6. http://dx.doi.org/10.1200/jco.2018.36.5_suppl.6.

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6 Background: Limited data in cancer patients have suggested that chemotherapy and radiation impact local and systemic immune cell populations. Radiation therapy (RT) is known to deplete circulating lymphocytes but is thought to increase local antigen presentation. The dynamics of these competing effects on the kinetics of intratumoral infiltration and expansion of activated and immunoregulatory T cells are unknown. Methods: We prospectively evaluated intratumoral immune infiltration during fractionated RT using multi-spectral flow cytometry. Cervical brushings were obtained from 14 patients before (baseline) and during RT (week 1, 3 and 5). Cells collected from the cervical brushings were stained with a 16-color panel of antibodies that included markers to identify T cell and dendritic cell subsets with activation and suppressor molecules. Changes in immune cell subsets at different time points were evaluated and calculated using matched-pair analysis with Wilcoxon rank sum test. Results: CD3+ T cells declined over the first week of treatment (28% of CD3 at baseline, vs. 14.8% at week 1, p = 0.0273). The percentage of CD3+ cells subsequently increased at 3 weeks (25.6%) and 5 weeks (37.8%). Both CD8+ and CD4+ T cells underwent a decline at week 1 followed by expansion at week 3 and 5. Percentages of regulatory T cells (CD4+Foxp3+) showed a similar trend of reduction and further expansion but did not reach significance. The percentage of CD8+ T cells expressing the T cell activation marker CD69 and the cytotoxic protease Granzyme B (GrzB) continuously increased over time (CD69+: 11.8%, 27.7%, 38.7%, 57.5%, and GrzB+: 23.9%, 53.2%, 48.1%, 58.2%). While the percentage of dendritic cells (CD11c+ CD11b+) was stable during treatment, the subset of activated dendritic cells expressing CD86 increased at week 1 and subsequently declined (week 1, 19.1% vs week 5, 9.8%, p = 0.0642). Conclusions: Activated CD8+ effector T cells expand in the cervix during radiation therapy. Moreover, in the first week of treatment, CD8+ T cells contract while dendritic cells undergo activation suggesting this may be a critical time to intervene to maximize anti-tumor immunity.

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Dimitrova, Polina, Mariela Vasileva-Slaveva, Velizar Shivarov, Ihsan Hasan e Angel Yordanov. "Infiltration by Intratumor and Stromal CD8 and CD68 in Cervical Cancer". Medicina 59, n.º 4 (7 de abril de 2023): 728. http://dx.doi.org/10.3390/medicina59040728.

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Background and Objectives: The tumor microenvironment (TME) plays a major role in neoplastic development. Various types of cells can be found in the TME. These cells can be classified into two groups, immunosuppressive and immunostimulatory types, depending on the function they perform in the antitumor immune response (IR). By interacting both with each other and with tumor cells, different immune mechanisms are activated or inhibited, which can suppress or promote the development and progression of cervical cancer (CC). Our aim was to investigate some of the main components of the cellular immune response in TME—tumor-infiltrating cytotoxic T cells (Tc, CD8+) and tumor-associated macrophages (TAMs, CD68+)—in patients with CC. Materials and Methods: We analyzed 72 paraffin-embedded tumor tissues of patients diagnosed and treated at Medical University Pleven, Bulgaria. Patients were classified according to the 2018 FIGO (International Federation of Gynaecology and Obstetrics) classification. From each patient, we selected one histological slide with hematoxylin eosin staining. In a microscopic evaluation, CD8+ T lymphocytes and CD68+-positive macrophages were counted in the tumor and stroma of five randomly selected fields at ×40 magnification (HPF). We analyzed the relationship between intratumoral and stromal CD8 and CD68 expression and FIGO stage and N status. Results: There was no significant association between the expression levels of intratumoral and stromal CD68+ cells in the different FIGO stages and according to the lymph nodes’ involvement. For CD8+ cells, the association of stromal infiltration was also not found, but T intratumor infiltration was associated with a higher FIGO stage, despite the fact that the results did not reach significance (p = 0.063, Fisher test). Intratumoral CD8+ cells were significantly associated with positive N status, (p = 0.035). Discussion: The separation of tumor-infiltrating cytotoxic T cells and tumor-associated macrophages into intratumoral and stromal is inconsequential. In our study, the level of infiltration of CD68+ cells in tumors and stromata was not significantly associated with tumor progression or lymph node involvement. The results were different for CD8+ cells, in which levels of infiltration were associated with lymph nodes’ statuses. Conclusions: The separate evaluation of CD68+ immune cells in the TME as intratumoral and stromal is not beneficial for defining prognoses, since the presence of these cells is not associated with the patient’s stage. In our study, the presence of CD8+ cells was significantly associated with lymph node metastases. The prognostic value of the obtained results can be enriched with an additional study of the lymphocyte phenotype, including B and other subtypes of T lymphocytes, NK cells, as well as molecules involved in the immune response, such as HLA subtypes.

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Gao, Qiang, Shuang-Jian Qiu, Jia Fan, Jian Zhou, Xiao-Ying Wang, Yong-Sheng Xiao, Yang Xu, Yi-Wei Li e Zhao-You Tang. "Intratumoral Balance of Regulatory and Cytotoxic T Cells Is Associated With Prognosis of Hepatocellular Carcinoma After Resection". Journal of Clinical Oncology 25, n.º 18 (20 de junho de 2007): 2586–93. http://dx.doi.org/10.1200/jco.2006.09.4565.

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Purpose To investigate the prognostic value of tumor-infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs), in hepatocellular carcinoma (HCC) patients after resection. Patients and Methods CD3+, CD4+, CD8+, Foxp3-positive, and granzyme B-positive TILs were assessed by immunohistochemistry in tissue microarrays containing HCC from 302 patients. Prognostic effects of low- or high-density TIL subsets were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff. Results CD3+, CD4+, CD8+ TILs were associated with neither overall survival (OS) nor disease-free survival (DFS). The presence of low intratumoral Tregs in combination with high intratumoral activated CD8+ cytotoxic cells (CTLs), a balance toward CTLs, was an independent prognostic factor for both improved DFS (P = .001) and OS (P < .0001). Five-year OS and DFS rates were only 24.1% and 19.8% for the group with intratumoral high Tregs and low activated CTLs, compared with 64.0% and 59.4% for the group with intratumoral low Tregs and high activated CTLs, respectively. Either intratumoral Tregs alone (P = .001) or intratumoral activated CTLs (P = .001) alone is also an independent predictor for OS. In addition, high Tregs density was associated with both absence of tumor encapsulation (P = .032) and presence of tumor vascular invasion (P = .031). Conclusion Tregs are associated with HCC invasiveness, and intratumoral balance of regulatory and cytotoxic T cells is a promising independent predictor for recurrence and survival in HCC. A combination of depletion of Tregs and concomitant stimulation of effector T cells may be an effective immunotherapy to reduce recurrence and prolong survival after surgery.

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Zhang, Xinke, Suijing Wang, Run-Cong Nie, Chunhua Qu, Jierong Chen, Yuanzhong Yang e Muyan Cai. "Immune Microenvironment Characteristics of Urachal Carcinoma and Its Implications for Prognosis and Immunotherapy". Cancers 14, n.º 3 (26 de janeiro de 2022): 615. http://dx.doi.org/10.3390/cancers14030615.

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Urachal carcinoma (UrC) is an exceedingly rare tumor and lacks effective treatment. Herein, we characterized an immune microenvironment characteristic of UrC in detail and identified its implications for prognosis and immunotherapy. In total, 37 resections of UrC were stained for CD20, CD3, CD4, CD8, FOXP3, CD68, HLA-DR, CD163, PD1, and PD-L1, as well as mismatch repair protein including MSH2, MSH6, MLH1, and PMS2 by immunohistochemistry. Intratumoral and peritumoral immune cell densities or the proportion of PD1 and PD-L1 expression alongside MSH2, MSH6, MLH1, and PMS2 status were manually evaluated using the whole slide. UrC patients with the number of tertiary lymphoid structures (TLS) per slide tended to be higher in tumors with dMMR (p = 0.1919), and tumors with higher number of TLS tended to have longer OS (p = 0.0940) and DFS (p = 0.0700). High densities of CD3+ T, CD8+ T, and CD68+ cells were significantly associated with worse OS and DFS (both p<0.05). Increased intratumoral (p = 0.0111) and peritumoral (p = 0.0485) CD8+ T cell densities were significantly associated with PD-L1 expression or increasing proportion of PD-L1 expression on immune cells. Similarly, increased intratumoral (p = 0.0008) and peritumoral (p = 0.063) CD8+ T cell densities were significantly associated with increasing proportion of PD1 expression on immune cells. Tumors with PD-L1 positive expression on immune cells had a significantly increased proportion of PD1 expression (p = 0.0121). High peritumoral CD8+ T cell density (>73.7/mm2) was significantly associated with worse OS (p = 0.0120) and DFS (p = 0.00095). The number of TLS seems to be considered not only as histopathological characteristics in predicting MMR status of UrC, but also as a prognostic or therapeutic biomarker, and we also provide some important suggestions for targeting PD-1/PD-L1 checkpoint in UrC.

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Teses / dissertações sobre o assunto "Intratumoral CD8 T cells"

PARTINI, BIANCA. "Investigation of intratumoral cd8+ t cell spatiotemporal localization and function". Doctoral thesis, Università Vita-Salute San Raffaele, 2023. https://hdl.handle.net/20.500.11768/136738.

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CD8+ T cells play a crucial role in controlling liver tumours, such as hepatocellular carcinoma (HCC) however we have only limited knowledge of the precise dynamics of their interactions with hepatic parenchymal and non-parenchymal cells at the single-cell level. Previous work from our laboratory, demonstrated that in the context of HBV-expressing hepatocytes circulating effector CD8+ T cells (Teff) perform their immune surveillance function recognizing the antigen and kill virus-expressing hepatocytes extending cytoplasmic protrusions through endothelial fenestrations while still within liver sinusoids. Here we dissected whether similar or different mechanisms govern the capacity of Teff to home, migrate, recognize the antigen, and exert effector function within HCC. The first effort to dissect the project was the establishment of a new murine model of spontaneous HCC in which just the transformed hepatocytes express a nominal antigen, the oncogene SV40 large T antigen (TAg) and a fluorescent protein. We were able to obtain mice that develop spontaneous HCC lesions, highly proliferating and spread in a normal liver parenchyma. After the adoptive transfer of in vitro differentiated TAg-specific Teff in tumor-bearing mice, we observed that just some mice respond to the cytotoxic activity of the transferred cells, eliminating partially or completely the tumor, while in other mice the adoptive transferred cells have no beneficial effect on the tumor elimination. Thus, using a mathematical approach, we managed to pick the lesion volume as the fundamental parameter to predict the fate of each single HCC lesion: we called “responders” (R) the HCC lesions that are responsive to the cytotoxic activity of the TAg-specific Teff, with a single lesion volume <10 mm3, while we called “non-responders” (NR) the lesions that are not responding and have a single HCC lesion volume > 100mm3. We then studied the determinants that confer the therapeutic activity to the TAg-specific Teff in R and the ones that dampen the therapeutic activity in the NR lesions. Our main finding was that the vessel phenotype was completely different in R and NR. Our data support the hypothesis that some anatomic, hemodynamic, and environmental features acquired by each individual HCC lesion, during their growth, can influence their responsiveness to the Teff killing. The innovative nature of our work will elucidate new mechanisms whereby Teff fail to exert their immune function and cytotoxic activity in tumorigenic liver.
Le cellule T CD8+ giocano un ruolo cruciale nel controllo dei tumori del fegato come l’epatocarcinoma, tuttavia, abbiamo una conoscenza limitata delle precise interazioni a livello di singola cellula tra le cellule T CD8+ e le cellule parenchimali e non parenchimali del fegato. Precedenti studi del nostro laboratorio hanno dimostrato che, nel contesto in cui gli epatociti esprimono HBV, le cellule circolanti T CD8+ effettrici (Teff) svolgono l’attività di immuno sorveglianza riconoscendo l’antigene ed esercitando un’attività citotossica verso gli epatociti che esprimono il virus. E’ stato infatti dimostrato che queste cellule sono capaci di estendere protrusioni citoplasmatiche attraverso le fenestrature delle cellule endoteliali rimanendo all’interno del lume sinusoidale. In questo progetto studiamo quindi se un meccanismo simile è coinvolto nella capacità delle Teff di migrare, riconoscere l’antigene e svolgere le proprie funzioni effettrici nel contesto di epatocarcinoma. Il primo obbiettivo di questo studio è stato quello di creare un nuovo modello di epatocarcinoma spontaneo in cui solo le cellule neoplastiche esprimessero sia dei marker fluorescenti (ZsGreen e TdTomato) che l’oncogene SV40 large T-antigen (TAg). Siamo riusciti ad ottenere dei topi che sviluppassero epatocarcinomi spontanei ed altamente proliferanti sparsi in tutto il parenchima sano del fegato. Dopo aver differenziato in vitro le Teff specifiche per l’antigene TAg (TCR-I Teff), abbiamo trasferito queste cellule in topi in cui era presente il tumore e abbiamo osservato che solo alcuni topi rispondevano totalmente o parzialmente all’attività citotossica delle cellule trasferite, le quali erano in grado di eliminare il tumore. Questo effetto era correlato alla dimensione di ogni singola lesione tumorale. Infatti, usando un approccio matematico multi-parametrico abbiamo scoperto che il trasferimento delle cellule TCR-I Teff era efficace solo in lesioni neoformate con un volume < 10 mm3 (lesioni responder [R]). Invece, quando il volume della lesione era > 100 mm3, il tumore non rispondeva alla terapia cellulare e continuava a crescere (lesioni non-responder [NR]). Abbiamo quindi deciso di studiare i fattori in grado di conferire alle nostre cellule effettrici un’attività terapeutica nei R e quelli in grado di frenare la loro efficacia nelle lesioni NR. Il principale risultato che abbiamo ottenuto riguarda la differenza del fenotipo della vascolatura tra lesioni R e NR. I nostri dati supportano infatti l’ipotesi che alcune caratteristiche anatomiche, emodinamiche e ambientali acquisite dai tumori durante la loro crescita possano influenzarne la responsività alla terapia delle Teff. La natura innovativa del nostro lavoro chiarirà nuovi meccanismi con cui le Teff effettuano immuno sorveglianza ed esercitano le loro funzioni effettrici nel contesto di tumore epatico.

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Cinier, Justine. "Importance et potentiel thérapeutique d'un nouveau couple récepteur-ligand dans l'inhibition des lymphocytes T CD8 par les lymphocytes T régulateurs dans les tumeurs". Electronic Thesis or Diss., Lyon 1, 2024. http://www.theses.fr/2024LYO10336.

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La présence de lymphocytes T (LT) CD8 dans le microenvironnement tumoral (TME) corrèle avec un bon pronostic dans de nombreux types de cancers solides. En périphérie, les LT régulateurs (Treg) jouent un rôle majeur dans le maintien d’une homéostasie immunitaire et empêchent le développement de pathologies auto-immunes. Néanmoins, dans le TME, les Treg (TA-Treg) ont un impact pronostic défavorable en inhibant la réponse immunitaire antitumorale. Sur le plan thérapeutique, il est indispensable d’éliminer ces TA-Treg ou leur fonction pour restaurer une réponse immunitaire antitumorale efficace. Pour cela, il reste important d’identifier des molécules membranaires permettant le ciblage sélectif de ces TA-Treg sans affecter les Treg périphériques pour éviter toute réaction auto-immune. L’analyse de données publiques de scRNA-seq comparant les LT (Treg, CD8, CD4) de tumeur, tissu sain et sang, a permis d’identifier l’expression sélective de CD177 par une population de TA-Treg dans plusieurs tumeurs solides. Si cette glycoprotéine est impliquée dans l’extravasation et la survie des neutrophiles, son rôle sur les Treg n’a été que peu décrit hormis dans quelques études confirmant l’expression de CD177 sur les TA-Treg dans plusieurs types tumoraux et montrant un effet suppresseur de ces TA-Treg CD177+ dans des cocultures avec des LT CD4 naïfs. Néanmoins, la caractérisation phénotypique et fonctionnelle de ces Treg reste peu explorée. CD177 interagit avec PECAM-1 qui est impliqué dans la transmigration des LT par interaction homophilique des domaines extracellulaires distaux immunoglobuline-like (IgD1/D2) avec les cellules endothéliales. De plus, il a été décrit que l’interaction avec le IgD6 extracellulaire de PECAM-1, zone de liaison de CD177, transmet un signal négatif via les motifs intracellulaires inhibiteurs (ITIM) et le recrutement de SHP2 qui bloque la signalisation TCR et la prolifération des LT. La réanalyse de données publiques de scRNA-seq de LT intra-tumoraux montre la restriction de l’expression de PECAM1 à des clusters de LT CD8 effecteurs mémoires suggérant qu’ils pourraient être la cible de la fonction immunosuppressive des Treg CD177+ dans le TME. Ainsi, dans l’objectif d’identifier un mécanisme de suppression des Treg spécifique des LT CD8 effecteurs dans l’environnement tumoral il est important de caractériser de manière approfondie ces TA-Treg CD177+ et d’identifier leurs interactions avec les LT CD8 PECAM-1+ dans le TME et leur impact sur la fonction de ces LT CD8. Ce travail de thèse a permis de démontrer, dans plusieurs types tumoraux, que CD177 identifie une population de Treg spécifiques de la tumeur, avec un phénotype activé. PECAM-1, la cible de CD177, est exprimé dans le TME par des LT CD8 effecteurs polyfonctionnels (GzmK, IFNү, TNFα), à forte capacité de prolifération. In situ sur coupe de tumeurs, des analyses de multi-immunofluorescence ont montré la colocalisation des Treg CD177+ et des LT CD8 PECAM-1+ au niveau du stroma tumoral, suggérant un lien entre ces deux populations. Par ailleurs, l’engagement de PECAM-1 IgD6, domaine de liaison de CD177, réduit l’activation et les fonctions des LT CD8 PECAM-1+ induites par le signal TCR en diminuant pZAP-70 et la sécrétion d’IFNү. Enfin, des premiers résultats sur tumeur ont montré que la culture de LT CD8 avec des TA-Treg CD177+ diminue la prolifération et la sécrétion d’IFNγ par les LT CD8 PECAM-1+ et l’ajout d’un anti-CD177 permet de lever en partie cette inhibition, suggérant le rôle de l’axe [CD177/PECAM-1] dans l’inhibition des LT CD8 PECAM-1+ par les TA-Treg CD177+. L’interaction [CD177/PECAM-1] représente la première mise en évidence d’un couple récepteur/ligand membranaire impliqué dans l’inhibition sélective des LT CD8 effecteurs par les TA-Treg dans le TME et CD177 apparait comme une cible prometteuse pour lever spécifiquement la suppression médiée par les Treg dans le TME sans altérer ceux de la périphérie
The presence of CD8 T cells in the tumor microenvironment (TME) correlates with good prognosis in many types of solid cancers. In the periphery, regulatory T cells (Treg) play a major role in maintaining immune homeostasis and preventing the development of autoimmune pathologies. However, in the TME, Treg (TA-Treg) have an unfavorable prognostic impact by inhibiting the anti-tumor immune response. Therapeutically, it is essential to eliminate these TA-Treg or their function to restore an effective anti-tumor immune response. For this, it remains important to identify membrane molecules allowing the selective targeting of these TA-Treg without affecting the Treg present in the periphery to avoid any autoimmune reaction. The analysis of public scRNA-seq data comparing T cells (Treg, CD8, CD4) from tumor, healthy tissue and blood, made it possible to identify the selective expression of CD177 by a subpopulation of TA-Treg in different solid tumors. If this glycoprotein is known for its involvement in the extravasation and survival of neutrophils, its role on Treg has been little described except in a few studies confirming the expression of CD177 on TA-Treg of several types of tumors and showing a suppressive impact of CD177+ TA-Treg in cocultures with naïve CD4 T cells. However, the phenotypic and functional characterization of these Treg remains little explored. CD177 interacts with PECAM-1 which is involved in T cells transmigration through homophilic interaction of distal extracellular immunoglobulin-like domains (IgD1/D2) with endothelial cells. Furthermore, it has been described that interaction with extracellular PECAM-1 IgD6, CD177 binding site, transmits a negative signal via inhibitory intracellular motifs (ITIM) and recruitment of SHP2 which blocks TCR signaling and the proliferation of T cells. Reanalysis of public scRNA-seq data from intra-tumoral T cells shows the restriction of PECAM1 expression to clusters of memory effector CD8 T cells suggesting that they could be the target of the immunosuppressive function of CD177+ Treg in the TME. Thus, with the aim of identifying a Treg suppression mechanism specific to effector CD8 T cells in the TME, it is important to characterize in depth these CD177+ TA-Treg and to identify their interactions with PECAM-1+ CD8 T cells in the TME and their impact on the function of these CD8 T cells. This thesis work demonstrated, in several tumor types, that CD177 identifies a population of TA- Treg, with an activated phenotype. PECAM-1, the target of CD177, is expressed in the TME by polyfunctional effector CD8 T cells (GzmK, IFNγ, TNFα) with a high proliferation capacity. In situ on tumor sections, multi-immunofluorescence analyses showed the colocalization of CD177+ Treg and PECAM-1+ CD8 T cells in the tumor stroma, suggesting a link between these two populations. Furthermore, engagement of PECAM-1 IgD6, CD177 binding domain, reduces the activation and functions of PECAM-1+ CD8 T cells induced by the TCR signal by decreasing pZAP-70 and IFNү secretion. Finally, initial results on tumors have shown that the culture of CD8 T cells with CD177+ TA-Treg reduces the proliferation and secretion of IFNγ by PECAM-1+ CD8 T cells and the addition of an anti-CD177 makes it possible to partly rescue this inhibition, suggesting the role of the [CD177/PECAM-1] axis in the inhibition of PECAM-1+ CD8 T cells by CD177+ TA-Treg. The [CD177/PECAM-1] interaction represents the first demonstration of a membrane receptor/ligand pair involved in the selective inhibition of CD8 T cells effectors by TA-Treg in the TME and CD177 appears as a promising target to specifically raise suppression mediated by TA-Treg in the TME without altering those in the periphery

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Granier, Clémence. "Expression de récepteurs inhibiteurs sur les lymphocytes T infiltrant les tumeurs du rein : signification biologique et clinique Multiplexed immunofluorescence analysis and quantification of intratumoral PD-1+ Tim-3+ CD8+ T cells Tim-3 expression on tumor-infiltrating PD-1+CD8+ T cells correlates with poor clinical outcome in renal cell carcinoma". Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB183.

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L'expression de récepteurs inhibiteurs tels PD-1, TIM-3, LAG-3, TIGIT sur les lymphocytes T participe à l'immunosuppression dans l'environnement tumoral. Le ciblage de PD-1 par les immunothérapies anti-PD-1/PD-L1 notamment révolutionne depuis peu la prise en charge de nombreux types de cancers en particulier dans le mélanome, cancer du poumon et aussi du rein. Dans la plupart des cancers comme dans celui du poumon et le mélanome, l'infiltrat CD8 et la réponse Th-1/IFN-gamma sont associés à un meilleur pronostic, contrairement aux tumeurs du rein et aux hémopathies. Les travaux de ma thèse s'intéressent à la caractérisation de l'expression des récepteurs inhibiteurs des lymphocytes, notamment PD-1 et TIM-3 dans le carcinome rénal et dans le lymphome. Mes travaux de thèse ont été réalisés avec des outils d'exploration du microenvironnement tumoral permettant une analyse multiplexe de nombreux paramètres in situ. En théorie jusqu'à 7 protéines peuvent être mises en évidence à la fois, j'ai pu mettre au point des comarquages de 4 protéines membranaires et/ ou nucléaires + Dapi ainsi que la détection d'ARN in situ dans les tumeurs. L'utilisation d'un outil technologique de microscopie à fluorescence multispectrale a permis une étude fine de la coexpression de PD-1 et Tim-3 sur les lymphocytes T CD8 (LT-CD8) grâce à la visualisation aisée de la colocalisation de ces 3 marqueurs. De la même façon, j'ai mis en évidence de l'expression de leurs ligands PD-L1 et Galectin-9 (Gal-9) dans l'environnement des tumeurs du rein. J'ai démontré que la co-expression de Tim-3 et PD-1 sur les CD8 dans le carcinome rénal avait un rôle délétère aussi bien sur le plan (i) fonctionnel puisque les LT-CD8 sécrétaient moins d'IFN-gamma, (ii) et clinique puisque les patients présentant un infiltrat de LT-CD8 double positifs pour PD-1 et TIM-3 récidivaient plus fréquemment. La présence des ligands PD-L1 et Gal-9 a été mise en évidence dans l'environnement tumoral laissant suggérer des interactions possibles avec les récepteurs inhibiteurs exprimés par les LT. J'ai également caractérisé les LT-CD8 PD-1+ TIM-3+ dans les lymphomes en combinant un marquage CD20 (quadruple + Dapi). Selon le type de lymphome, TIM-3 était coexprimé avec PD-1 à la surface des CD8 et plus ou moins au contact avec les cellules lymphomateuses CD20+. D'autre part, lorsque TIM-3 était coexprimé, les LT-CD8 étaient plus volontiers proliférant (comarquage Ki-67) en comparaison aux PD-1+ TIM-3-. Afin de poursuivre dans la caractérisation Th-1/IFN-gamma, j'ai élaboré la mise au point de la détection d'ARN dans les lymphocytes T in situ dans la tumeur, permettant de faire des liens avec leur fonctionnalité. Au total mes travaux de thèse ont permis de mettre en évidence des biomarqueurs immunologiques composites en lien avec l'expression des récepteurs inhibiteurs PD-1 et/ou TIM-3 et la perte de fonctionnalité (IFN-gamma) des lymphocytes T intratumoraux
It has been mainly described that the inhibitory receptors coexpression (PD-1, TIM-3, LAG-3, TIGIT) by lymphocytes in the tumor microenvironment (TME) induces a local immunosuppression. Targeting these receptors particularly PD-1 and its ligand PD-L1 is of great clinical benefit in cancer many types treatment (melanoma, renal and lung cancer in particular). In the most cases of cancer, like melanoma and lung cancer, a CD8-T cell and Th-1/IFN-gamma response is of good prognosis. But this is not the case in renal cancer and in hemopathies. My PhD work attempts to characterize clinical and biological implication of PD-1 and TIM-3 expression by intra-tumor lymphocytes in the setting of renal cancer and lymphoma. My PhD work has been conducted thanks to new methods of multiplexed characterization of the TME. Multispectral immunofluorescence lead to identify 7 parameters at the same time, and in this study I elaborated the identifications of lymphocytes markers in situ within the tumor: 4 membrane and/or nuclear proteins + nuclei (Dapi counterstain) and also coupled with the RNA detection. This tool allows me to accurately study the coexpression of PD-1 and TIM-3 at the CD8-T cell surface thanks to colocalisation identification and counting of these 3 markers. With the same method, I found that PD-L1 and Gal-9, which are PD-1 and TIM-3 ligands, were also expressed in the TME of renal carcinoma. I found that the coexpression of TIM-3 together with PD-1 in the CD8-T cells had a double relevance (i) at functional level, CD8-T cells were less able to secrete gamma-IFN (ii) at clinical level, patients harboring a higher infiltrate were more likely to relapse. The presence of PD-L1 and Gal-9 suggested interactions with inhibitory receptors of T cells. I also characterized CD8-T cells expressing PD-1 and TIM-3 in lymphomas, combining a CD20 staining (quadruple staining + Dapi). TIM-3 was more or less expressed depending of the lymphoma type near to CD20+ cells. TIM-3 PD-1 CD8-T cells were more likely Ki-67+ compared to TIM-3- cells, suggesting a more proliferative capacity. In order to continue the characterization of the Th-1/gamma-IFN-gamma immune response, I elaborate a technic to detect the gamma-IFN RNA in situ, together with lymphocytes staining, allowing the exploration of functionality within the tumor. To summarize, during my PhD work I could characterize composite immune biomarkers linked to the functionality of CD8-T cell and gamma-IFN Th-1 response

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Sepulveda, Homero. "Activation requirements for CD8 T cells /". Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1998. http://wwwlib.umi.com/cr/ucsd/fullcit?p9907780.

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Mühle, Kerstin. "Interaction of CD8+CD40L+ T cells with B cells". Doctoral thesis, Humboldt-Universität zu Berlin, 2018. http://dx.doi.org/10.18452/19127.

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ZTLs vermitteln die Eliminierung von infizierten und entarteten Zellen durch Apoptose. Neuste Erkenntnisse unserer Gruppe haben gezeigt, dass eine Subpopulation der CD8+ T-Zellen, anstelle der zytotoxischen Marker das Oberflächenmolekül CD40L exprimiert. Die Expression von CD40L ist bislang als Schlüsselmolekül für die CD4+ T-Zell vermittelte Hilfe bekannt, welche durch Bindung an den CD40 Rezeptor auf anderen Immunzellen induziert wird. Das von den CD4+ T–Zellen ausgehende CD40L Signal ist besonders für die T-Zell abhängige B-Zell Aktivierung und die Bildung von Keimzentren essentiell, in denen B-Zellen heranreifen und hochaffine Antikörper produzieren um den Organismus vor eindringenden Erregern zu schützen. Aufgrund der CD40L-assoziierten Helferfunktion sollte in dieser Arbeit untersucht werden, welche Auswirkungen die Interaktion von CD8+CD40L+ T-Zellen mit B Zellen hat. In in vitro Studien konnte gezeigt werden, dass 50% der antigen-spezifischen CD8+ T-Zellen nach Aktivierung durch B-Zellen CD40L hochregulieren. Sowohl auf RNA- als auch auf Proteinebene induzierten CD8+CD40L+ T-Zellen einen B-Zell Phänotyp, der stark dem von CD4+ T-Zellen stimulierten B-Zellen ähnelte. In Infektionsversuchen mit dem B-Zell-trophen Virus MHV-68 konnte gezeigt werden, dass transgene Mäuse mit CD40L defizienten CD8+ T-Zellen im Vergleich zu Kontrolltieren eine signifikante Reduktion der Keimzentrums-B-Zellen in den Lymphknoten der oberen Halsregion aufweisen. Eine genauere Betrachtung des B-Zell Repertoires von IgG Gedächtniszellen ergab jedoch, dass die Sequenzen der IGHJ3 Genfamilie bevorzugt für die Modifikation der CDR3 Region in Mäusen mit CD40L defizienten CD8+ T-Zellen verwendet wird, die eine entscheidende Rolle bei der Antigenerkennung spielt. Zusammengefasst kann mit dieser Arbeit zum ersten Mal gezeigt werden, dass CD8+CD40L+ T-Zellen Helferfunktionen durch Unterstützung der B-Zell Aktivierung und Bildung von Keimzentren übernehmen können.
CTLs are important for the elimination of infected and degenerated cells by inducing apoptosis of the target cells. Recently our group identified a sub-population of CD8+ T cells expressing CD40L instead of common CTL markers. To that date, transient CD40L expression on T cells has been only described as a function of activated CD4+ T cells, which displays this key molecule for CD4+ T cell mediated help by binding to the CD40 receptor on other immune cells. Particularly, CD40L signaling provided by CD4+ T cells is indispensable for T cell dependent B cell activation and GC responses, which generate B cells secreting high affinity antibodies that protect the host from invading pathogens. Due to its associated helper functions, this thesis aimed to dissect whether CD40L positive CD8+ T cells are restricted to cytotoxic killing or if this sub-population possesses similar properties as CD4+ T cells when interacting with B cells. In vitro co-culture experiments showed that 50% of murine antigen specific CD8+ T cells up-regulated CD40L upon activation by antigen presenting B cells. When compared to CD40L deficient CD8+ T cells, the interaction of CD8+ CD40L+ T cells induced remarkable changes in B cells on the RNA and protein level and triggered a B cell phenotype resembling that of B cells primed by CD4+ T cells. By the infection of mice with the B cell trophic virus MHV-68, it was found that E8IcrexCD40Lflox transgenic mice lacking CD40L only on matured CD8+ T cells, exhibited a significant decrease of GC B cells in superficial cervical lymph nodes at the acute state of infection compared to WT mice. A closer look into the memory B cell repertoire revealed a preferred usage of the murine IGHJ3 gene family that modifies the CDR3 and thus the recognition groove of the B cell antibody in E8IcrexCD40Lflox mice. In summary, this work provides sufficient evidence that CD8+ CD40L+ T cells adopt helper-like functions by supporting B cell activation and subsequent GC formation.

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Jarvis, Lorna Beth. "Autoreactive CD8+ regulatory T cells in spondyloarthritis". Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.605067.

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There have been substantial advances in our understanding of the CD4+CD25+ regulatory T cell subset, but the possibility of an equivalent regulatory subset within the CD8+ T cell population has received less attention. In the course of studies investigating immunological abnormalities in patients with the inflammatory arthritis Ankylosing Spondylitis (AS), novel human CD8+ T cells that have a regulatory phenotype and function have been identified. CD8+/TCRαβ+ T cells were isolated from the peripheral blood of both AS patients and healthy donors and subsequently expanded as T cell lines using antilogous LPS activated dendritic cells. These lines contained IL-4 producing CD8+ T cells which were then cloned non-specifically by limiting dilution. Conventional CD8+ T cells are cytotoxic but these clones were not. They proliferated and produced cytokines in an autoreactive HLA class I restricted fashion; the cytokines produced included IL-4, IL-5 and TGFβ1, but not IFN-γ or IL-10. The clones expressed markers commonly associated with CD4+CD25+ regulatory T cells, including high levels of CTLA-4 and Foxp3. They suggested IFN-γ production and proliferation by CD4+ T cells in vitro in a cell contact dependent manner, which appeared to involve surface CTLA-4 since suppression could be blocked using an anti-CTLA-4 mAb. Increased numbers of these IL-4+ CD8+ T cells were found in AS patients’ PBMC stimulated directly ex vivo compared to healthy donors, and high numbers correlated with decreased numbers of pro-inflammatory IFN-γ producing T cells, suggesting they may actively regulate inflammation in vivo. Thus, human CD8+ regulatory T cells may be up-regulated in the peripheral blood under certain pathological conditions such as in response to chronic inflammation. AS is a remitting and relapsing inflammatory disease; therefore it is possible that these cells contribute to periods of remission by actively regulating inflammation in vivo.

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Wangteeraprasert, Apirath. "CD8+ T-cells responses in Dengue virus infection". Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/39398.

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Dengue virus, which has four serotypes, has several clinical manifestations including asymptomatic infection, a self-limiting febrile illness termed dengue fever (DF) and a severe form characterized by plasma leakage termed dengue hemorrhagic fever (DHF). The pathogenesis of DHF is not fully understood and many studies have shown that it is more prevalent during secondary infection. In addition to a mechanism termed antibody dependent enhancement (ADE), the role of T-cells in the pathogenesis of dengue also has been investigated. It has been hypothesized that upon secondary infection dengue-specific memory T-cells generated during a previous infection, which are cross-reactive and have low avidity for the current serotype dominate the T-cell response. This phenomenon is called 'Original antigenic sin' and the consequence of this low avidity T-cell response may be ineffective viral elimination leading to increased production of inflammatory cytokines which could cause plasma leakage. To study CD8+ T-cell responses to dengue-peptide variants, HLA-A11-restricted NS3 133-142-specific T-cell clones were generated and their cytotoxicity, proliferation and cytokine production in response to variant epitopes was tested. The results support that the magnitude of T-cell responses is related to the strength of the TCR-peptide-MHC interaction. AG129 mice, which lack both IFN (symbol missing) and IFN (symbol missing) receptors, show susceptibility to dengue virus infection and develop symptoms seen during human infection such as vascular leakage. This allows for investigation of the role of T-cell responses generated towards sequential infections with well defined serotypes. Experiments that would be very difficult to carry out in human dengue patients. Splenocytes from sequentially infected AG129 mice were assayed for their response to whole dengue proteins from serotype 1 and 2 virus. New epitopes were identified and CD8+ T-cell lines and clones were generated and their functions studied using peptide variants. The results showed that dengue-specific cross-reactive memory CTLs displayed better recognition of epitopes encountered during primary immunisa tion as compare to those recognised during secondary immunisation, which supports the idea of original antigenic sin in dengue-specific CD8+ T -cells. In conclusion, this study focuses on cross-reactive dengue-specific CD8+ T-cells and their functions when recognizing heterologous dengue peptides to clarify their role in pathogenesis.

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Istaces, Nicolas. "Transcriptional control of innate memory CD8+ T cells". Doctoral thesis, Universite Libre de Bruxelles, 2019. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/295204.

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CD8+ T cells are essential for host protection against intracellular pathogens and tumors. During antigen-driven responses, CD8+ T cell fate is governed by transcriptional and epigenetic processes that allow naïve CD8+ T cells to develop into a wide range of effector and conventional memory cell subsets. Over the last decades, novel techniques and major efforts led to a better understanding of the origin, nature, and short- and long-term effects of these processes on individual CD8+ T cells. Under certain conditions, naïve CD8+ T cells can acquire memory phenotype and functions in an antigen-independent manner. Although homeostatic cytokines and initial activation pathways that drive the development of these unconventional memory cells had been identified, the ensuing transcriptional profile of these cells and their degree of similarity with conventional memory cells remained ill-defined. The epigenetic events that accompany unconventional memory formation were also not known.Here, we show that innate memory cells, a type of thymic unconventional memory cells, are transcriptionally close to conventional memory cells but only partially epigenetically programmed toward the full memory fate. We also show that the sole overexpression of the transcription factor Eomesodermin (EOMES), a master regulator of effector and conventional memory cells, is able to drive many of the phenotypical, functional, transcriptional, and epigenetic features of innate memory cells, and to induce the recruitment of BRG1, a member of chromatin remodeling complexes, to innate memory gene regulatory regions. We further show that the in vivo interleukine-4-dependent development of innate memory cells is largely dependent on BRG1. We bring to light that, in innate memory cells, EOMES is recruited in many instances to genomic regions previously bound by the transcription factor RUNX3. Overall, we provide insights into the mechanisms that allow memory cell formation and T cell receptor stimulation to be uncoupled.
Doctorat en Sciences médicales (Médecine)
info:eu-repo/semantics/nonPublished

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Su, Charles. "Endogenous Memory CD8 T Cells in Cardiac Transplantation". Case Western Reserve University School of Graduate Studies / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1404079898.

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Raveney, Ben J. E. "Interactions between CD8+ T cells and bone marrow-derived dendritic cells". Thesis, University of Bristol, 2006. http://hdl.handle.net/1983/dbbc656f-a103-4787-aeb9-f203c3f0082b.

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Livros sobre o assunto "Intratumoral CD8 T cells"

Ford, Megan. The role and mechanism of B6/1pr TCR[alpha beta]+CD4-CD8- T cells in immune response regulation. Ottawa: National Library of Canada, 2001.

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Kay, Lyndsey Sara. Anti-B-cell lymphoma activity mediated by CD3+CD4-CD8- T cells activated in vitro or in vivo. Ottawa: National Library of Canada, 2003.

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Negative immunoregulatory role of CD8 T cells in peripheral tolerance. [New York]: [Columbia University], 1993.

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Woodworth, Joshua. Class I MHC-restricted CD8+ T cells and host immunity to Mycobacterium tuberculosis. 2008.

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Datta, Syamal Kumar, Antonio La Cava, David A. Horwitz e Ciriaco A. Piccirillo, eds. Generating and Sustaining Stable Autoantigen-specific CD4 and CD8 Regulatory T Cells in Lupus. Frontiers Media SA, 2022. http://dx.doi.org/10.3389/978-2-88974-788-7.

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Blaser, Claudine. Indentification and characterisation of differentially expressed genes in naive and activated CD8⁺ T cells. 1999.

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Arosa, Fernando A., ed. On the Origin and Function of Human NK-like CD8+ T Cells: Charting New Territories. Frontiers Media SA, 2018. http://dx.doi.org/10.3389/978-2-88945-396-2.

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Dimier-Poisson, Isabelle. Major Role for CD8+T Cells in the Protection Against Toxoplasma gondii Following Dendritic Cell Vaccination. INTECH Open Access Publisher, 2012.

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Koh, Dow-Rhoon. The role of CD4+, CD8+ and CD4-8-T cells in murine experimental allergic encephalomyelitis and lupus. 1993.

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Young, Kevin J. The role and mechanisms of CD3+CD4-CD8-regulatory T cells in the suppression of allogeneic immune responses. 2003.

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Capítulos de livros sobre o assunto "Intratumoral CD8 T cells"

Kotlyar, David. "CD8 T Cells". In Cancer Therapeutic Targets, 131–42. New York, NY: Springer New York, 2017. http://dx.doi.org/10.1007/978-1-4419-0717-2_93.

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Kotlyar, David. "CD8 T Cells". In Cancer Therapeutic Targets, 1–12. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4614-6613-0_93-1.

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Munitic, Ivana, César Evaristo, Hsueh Cheng Sung e Benedita Rocha. "Transcriptional Regulation during CD8 T-Cell Immune Responses". In Memory T Cells, 11–27. New York, NY: Springer New York, 2010. http://dx.doi.org/10.1007/978-1-4419-6451-9_2.

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Boyman, Onur, Jae-Ho Cho e Jonathan Sprent. "The Role of Interleukin-2 in Memory CD8 Cell Differentiation". In Memory T Cells, 28–41. New York, NY: Springer New York, 2010. http://dx.doi.org/10.1007/978-1-4419-6451-9_3.

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Friese, Manuel A., e Lars Fugger. "CD8+ T Cells in Multiple Sclerosis". In Immune Regulation and Immunotherapy in Autoimmune Disease, 265–85. Boston, MA: Springer US, 2007. http://dx.doi.org/10.1007/978-0-387-36003-4_13.

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Out, Theo A., Francina L. de Pater-Huijsen, Henk M. Jansen e Chris J. Corrigan. "CD8 T Cells: Potential Therapeutic Targets?" In New Drugs for Asthma, Allergy and COPD, 233–36. Basel: KARGER, 2001. http://dx.doi.org/10.1159/000062177.

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Maherzi, C., F. Onodi, E. Tartour, M. Terme e C. Tanchot. "Strategies to Reduce Intratumoral Regulatory T Cells". In Oncoimmunology, 483–506. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-62431-0_29.

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Kalia, Vandana, Surojit Sarkar e Rafi Ahmed. "CD8 T-Cell Memory Differentiation during Acute and Chronic Viral Infections". In Memory T Cells, 79–95. New York, NY: Springer New York, 2010. http://dx.doi.org/10.1007/978-1-4419-6451-9_7.

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Zanetti, Maurizio, Paola Castiglioni e Elizabeth Ingulli. "Principles of Memory CD8 T-Cells Generation in Relation to Protective Immunity". In Memory T Cells, 108–25. New York, NY: Springer New York, 2010. http://dx.doi.org/10.1007/978-1-4419-6451-9_9.

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Kim, Edward Y., Stephen C. Juvet e Li Zhang. "Regulatory CD4– CD8– Double Negative T Cells". In Methods in Molecular Biology, 85–98. Totowa, NJ: Humana Press, 2010. http://dx.doi.org/10.1007/978-1-60761-869-0_6.

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Trabalhos de conferências sobre o assunto "Intratumoral CD8 T cells"

Fischer, Travis D., Caitlin D. Lemke-Miltner e George J. Weiner. "1027 Intratumoral injection of vidutolimod, an immunostimulatory virus-like particle, enhances the number of intratumoral and circulating tumor-specific CD8 T cells". In SITC 39th Annual Meeting (SITC 2024) Abstracts, A1148. BMJ Publishing Group Ltd, 2024. http://dx.doi.org/10.1136/jitc-2024-sitc2024.1027.

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Yamashita, Kimihiro, EIJI Fukuoka, Yutaka Sugita, Akira Arimoto, Akihiro Watanabe, Gousuke Takiguchi, Naoki Urakawa et al. "Abstract 2260: Radiotherapy enhances newly infiltrating CD8+T cells into tumor tissue to increase intratumor CD8+T cells and exert an anti-tumor effects". In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-2260.

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Kato, Takuya, Kazuhiro Noma, Yuki Katsura, Hiroaki Sato, Satoshi Kohmoto, Toshiaki Ohara, Hiroshi Tazawa, Yasuhiro Shirakawa, Masaru Inagaki e Toshiyoshi Fujiwara. "Abstract 1741: Cancer-associated fibroblasts regulate intratumoral CD8+/FoxP3+ T cells via interleukin 6 in the tumor immune microenvironment". In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-1741.

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Orlandella, Rachael M., Daniel L. Smith e Lyse A. Norian. "Abstract 504: Acarbose enhances intratumoral CD8 T cell responses in a pre-clinical model of kidney cancer". In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-504.

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Lammers, Marshall, Sean Judge, Lauren Farley, Khurshid Iranpur, Ryan Nielsen, Aryana Razmara, Arta Monjazeb, William Murphy e Robert Canter. "990 Context dependent effects of TIGIT expression on circulating versus intratumoral NK and CD8 T cells in mouse and human sarcoma models". In SITC 38th Annual Meeting (SITC 2023) Abstracts. BMJ Publishing Group Ltd, 2023. http://dx.doi.org/10.1136/jitc-2023-sitc2023.0990.

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Etxeberria, Inaki, Elixabet Bolaños, Alvaro Teijeira, Arantza Azpilicueta, Jose Ignacio Quetglas, Alfonso Rodriguez Sanchez-Paulete, Itziar Otano et al. "Abstract 2331: Intratumor adoptive transfer of IL-12 mRNA transiently engineered anti-tumor CD8+ T cells". In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-2331.

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Kalimutho, Murugan, e Kum Kum Khanna. "Abstract LB-256: PDGFRβ blockade bypasses resistance to combined MEK1/2-JAK2 inhibition in triple-negative breast cancer via intratumoral CD8+ T-cells infiltration". In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-lb-256.

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Relatórios de organizações sobre o assunto "Intratumoral CD8 T cells"

Knutson, Keith L. CD8 T Cells and Immunoediting of Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, agosto de 2008. http://dx.doi.org/10.21236/ada624685.

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Lee, Chung, Timothy Kuzel, Richard Meagher, Ximing Yang, Norm Smith e Qiang Zhang. Preparation for a Clinical Trial Using Adoptive Transfer of Tumor-Reactive TGF_Beta-Insensitive CD8+ T Cells for Treatment of Prostate Cancer. Fort Belvoir, VA: Defense Technical Information Center, julho de 2006. http://dx.doi.org/10.21236/ada462885.

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Lee, Chung. Preparation for a Clinical Trial Using Adoptive Transfer of Tumor-Reactive TGF_Beta-Insensitive CD8+ T Cells for Treatment of Prostate Cancer. Fort Belvoir, VA: Defense Technical Information Center, julho de 2006. http://dx.doi.org/10.21236/ada463479.

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cui, meng, zhiyong wan, jia yang, dan liao, junliang chen, yin xiang, zhiwei cui, yang yang e fanmin li. Prognostic significance of programmed cell death 1 expression on CD8-T cells in various cancers: a systematic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, novembro de 2024. http://dx.doi.org/10.37766/inplasy2024.11.0075.

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Banai, Menachem, e Gary Splitter. Molecular Characterization and Function of Brucella Immunodominant Proteins. United States Department of Agriculture, julho de 1993. http://dx.doi.org/10.32747/1993.7568100.bard.

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The BARD project was a continuation of a previous BARD funded research project. It was aimed at characterization of the 12kDa immunodominant protein and subsequently the cloning and expression of the gene in E. coli. Additional immunodominant proteins were sought among genomic B. abortus expression library clones using T-lymphocyte proliferation assay as a screening method. The 12kDa protein was identified as the L7/L12 ribosomal protein demonstrating in the first time the role a structural protein may play in the development of the host's immunity against the organism. The gene was cloned from B. abortus (USA) and B. melitensis (Israel) showing identity of the oligonucleotide sequence between the two species. Further subcloning allowed expression of the protein in E. coli. While the native protein was shown to have DTH antigenicity its recombinant analog lacked this activity. In contrast the two proteins elicited lymphocyte proliferation in experimental murine brucellosis. CD4+ cells of the Th1 subset predominantly responded to this protein demonstrating the development of protective immunity (g-IFN, and IL-2) in the host. Similar results were obtained with bovine Brucella primed lymphocytes. UvrA, GroE1 and GroEs were additional Brucella immunodominant proteins that demonstrated MHC class II antigenicity. The role cytotoxic cells are playing in the clearance of brucella cells was shown using knock out mice defective either in their CD4+ or CD8+ cells. CD4+ defective mice were able to clear brucella as fast as did normal mice. In contrast mice which were defective in their CD8+ cells could not clear the organisms effectively proving the importance of this subtype cell line in development of protective immunity. The understanding of the host's immune response and the expansion of the panel of Brucella immunodominant proteins opened new avenues in vaccine design. It is now feasible to selectively use immunodominant proteins either as subunit vaccine to fortify immunity of older animals or as diagnostic reagents for the serological survaillance.

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Leitner, Gabriel, e Naomi Balaban. Novel Immunotherapeutic Agent for the Treatment and Prevention of Staphylococcal Mastitis in Dairy Cows. United States Department of Agriculture, janeiro de 2009. http://dx.doi.org/10.32747/2009.7709880.bard.

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Staphylococci are the most common and costly mammary disease of dairy cattle worldwide. TRAP, a membrane associated 167AA protein, is highly conserved among staphylococci. The aims of this study were to test the safety and efficacy of recombinant TRAP (rTRAP) vaccine in dairy animals. The vaccine was safe as 2-3 subcutaneous injections of rTRAP (54–100μg) with adjuvant ISA 206 to cows and goats did not lead to any abnormal symptoms of sensitivity to the vaccine. The rTRAP vaccine was immunogenic and caused the induction of a humoral immune response that remained high for at least 160 days post second immunization. rTRAP vaccine also elicited a cell-mediated immune response (memory CD4+ and CD8+ T cells), as determined by lymphocyte proliferation assays. The rTRAP vaccine was efficacious as at parturition, only 13.5% heifers in the immunized group were infected with Staphylococcus chromogenes as compared to 42.9% in the non immunized group. Additionally, when cows were immunized in mid-lactation, the difference between somatic cell count (SCC) in immunized and control animals was profound (45±7 vs. 470±194, respectively). At the same time, the difference in milk yield was also evident (48.3±1.4 vs. 44.3±0.9 l/day, respectively). Put together, these studies indicate the value of the rTRAP vaccine in preventing new udder infections by staphylococci, which significantly lead to lowered SCC and some increase in milk yield. TRAP is conserved among all strains and species and is constitutively expressed in any strain of S. aureus or CNS tested so far, including those isolated from cows. TRAP may thus serve as a universal anti-staphylococcus vaccine.

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Ficht, Thomas, Gary Splitter, Menachem Banai e Menachem Davidson. Characterization of B. Melinensis REV 1 Attenuated Mutants. United States Department of Agriculture, dezembro de 2000. http://dx.doi.org/10.32747/2000.7580667.bard.

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Brucella Mutagenesis (TAMU) The working hypothesis for this study was that survival of Brucella vaccines was directly related to their persistence in the host. This premise is based on previously published work detailing the survival of the currently employed vaccine strains S19 and Rev 1. The approach employed signature-tagged mutagenesis to construct mutants interrupted in individual genes, and the mouse model to identify mutants with attenuated virulence/survival. Intracellular survival in macrophages is the key to both reproductive disease in ruminants and reticuloendothelial disease observed in most other species. Therefore, the mouse model permitted selection of mutants of reduced intracellular survival that would limit their ability to cause reproductive disease in ruminants. Several classes of mutants were expected. Colonization/invasion requires gene products that enhance host-agent interaction or increase resistance to antibacterial activity in macrophages. The establishment of chronic infection requires gene products necessary for intracellular bacterial growth. Maintenance of chronic infection requires gene products that sustain a low-level metabolism during periods characterized little or no growth (1, 2). Of these mutants, the latter group was of greatest interest with regard to our originally stated premise. However, the results obtained do not necessarily support a simplistic model of vaccine efficacy, i.e., long-survival of vaccine strains provides better immunity. Our conclusion can only be that optimal vaccines will only be developed with a thorough understanding of host agent interaction, and will be preferable to the use of fortuitous isolates of unknown genetic background. Each mutant could be distinguished from among a group of mutants by PCR amplification of the signature tag (5). This approach permitted infection of mice with pools of different mutants (including the parental wild-type as a control) and identified 40 mutants with apparently defective survival characteristics that were tentatively assigned to three distinct classes or groups. Group I (n=13) contained organisms that exhibited reduced survival at two weeks post-infection. Organisms in this group were recovered at normal levels by eight weeks and were not studied further, since they may persist in the host. Group II (n=11) contained organisms that were reduced by 2 weeks post infection and remained at reduced levels at eight weeks post-infection. Group III (n=16) contained mutants that were normal at two weeks, but recovered at reduced levels at eight weeks. A subset of these mutants (n= 15) was confirmed to be attenuated in mixed infections (1:1) with the parental wild-type. One of these mutants was eliminated from consideration due to a reduced growth rate in vitro that may account for its apparent growth defect in the mouse model. Although the original plan involved construction of the mutant bank in B. melitensis Rev 1 the low transformability of this strain, prevented accumulation of the necessary number of mutants. In addition, the probability that Rev 1 already carries one genetic defect increases the likelihood that a second defect will severely compromise the survival of this organism. Once key genes have been identified, it is relatively easy to prepare the appropriate genetic constructs (knockouts) lacking these genes in B. melitensis Rev 1 or any other genetic background. The construction of "designer" vaccines is expected to improve immune protection resulting from minor sequence variation corresponding to geographically distinct isolates or to design vaccines for use in specific hosts. A.2 Mouse Model of Brucella Infection (UWISC) Interferon regulatory factor-1-deficient (IRF-1-/- mice have diverse immunodeficient phenotypes that are necessary for conferring proper immune protection to intracellular bacterial infection, such as a 90% reduction of CD8+ T cells, functionally impaired NK cells, as well as a deficiency in iNOS and IL-12p40 induction. Interestingly, IRF-1-/- mice infected with diverse Brucella abortus strains reacted differently in a death and survival manner depending on the dose of injection and the level of virulence. Notably, 50% of IRF-1-/- mice intraperitoneally infected with a sublethal dose in C57BL/6 mice, i.e., 5 x 105 CFU of virulent S2308 or the attenuated vaccine S19, died at 10 and 20 days post-infection, respectively. Interestingly, the same dose of RB51, an attenuated new vaccine strain, did not induce the death of IRF-1-/- mice for the 4 weeks of infection. IRF-1-/- mice infected with four more other genetically manipulated S2308 mutants at 5 x 105 CFU also reacted in a death or survival manner depending on the level of virulence. Splenic CFU from C57BL/6 mice infected with 5 x 105 CFU of S2308, S19, or RB51, as well as four different S2308 mutants supports the finding that reduced virulence correlates with survival Of IRF-1-/- mice. Therefore, these results suggest that IRF-1 regulation of multi-gene transcription plays a crucial role in controlling B. abortus infection, and IRF-1 mice could be used as an animal model to determine the degree of B. abortus virulence by examining death or survival. A3 Diagnostic Tests for Detection of B. melitensis Rev 1 (Kimron) In this project we developed an effective PCR tool that can distinguish between Rev1 field isolates and B. melitensis virulent field strains. This has allowed, for the first time, to monitor epidemiological outbreaks of Rev1 infection in vaccinated flocks and to clearly demonstrate horizontal transfer of the strain from vaccinated ewes to unvaccinated ones. Moreover, two human isolates were characterized as Rev1 isolates implying the risk of use of improperly controlled lots of the vaccine in the national campaign. Since atypical B. melitensis biotype 1 strains have been characterized in Israel, the PCR technique has unequivocally demonstrated that strain Rev1 has not diverted into a virulent mutant. In addition, we could demonstrate that very likely a new prototype biotype 1 strain has evolved in the Middle East compared to the classical strain 16M. All the Israeli field strains have been shown to differ from strain 16M in the PstI digestion profile of the omp2a gene sequence suggesting that the local strains were possibly developed as a separate branch of B. melitensis. Should this be confirmed these data suggest that the Rev1 vaccine may not be an optimal vaccine strain for the Israeli flocks as it shares the same omp2 PstI digestion profile as strain 16M.

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