Journal articles: 'TCRBV'

1

Zhao, T. M., S. E. Whitaker, and M. A. Robinson. "A genetically determined insertion/deletion related polymorphism in human T cell receptor beta chain (TCRB) includes functional variable gene segments." Journal of Experimental Medicine 180, no. 4 (October 1, 1994): 1405–14. http://dx.doi.org/10.1084/jem.180.4.1405.

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Polymorphism in the human T cell receptor beta chain (TCRB) gene complex includes haplotypes with different numbers of TCRBV genes. An insertion/deletion related polymorphism (IDRP) in the human TCRBV region was found to involve TCRBV gene segments. Inserted TCRB haplotypes contain an additional 21.5 kb in which three TCRBV genes are encoded, members of the TCRBV7, TCRBV9, and TCRBV13 families. Two TCRBV gene segments were present only in inserted haplotypes; one of these, TCRBV7S3, is a functional gene and the other, TCRBV9S2(P), is a pseudogene because of an inframe termination colon. In addition, inserted haplotypes contain two identical copies of the TCRBV13S2 gene, whereas deleted haplotypes have only one copy. Deleted haplotypes could be subdivided into two types, deleted*1 and deleted*2, on the basis of sequence variations in TCRBV6S7 and TCRBV13S2 genes. Both deleted*1 and deleted*2 haplotypes contained the same number of TCRBV genes; both contain 60 genes of which 50 are functional, whereas, inserted haplotypes contained 63 genes of which 52 are functional. Comparisons of inserted region sequences with the homologous region in a deleted haplotype, and with sequences surrounding related TCRBV genes, revealed patterns of similarity that suggest insertion as well as deletion events have occurred in the evolution of the TCRBV gene complex. These data indicate that the genomic TCR repertoire is expanded in individuals who have inserted TCRBV haplotypes. The presence of additional TCRBV genes or, alternatively, the absence of certain TCRBV genes may have an impact upon immune responses and susceptibility to autoimmune diseases.

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Kiianitsa, Konstantin, Vladimir Lesnikov, Robert Jordan, and George E. Georges. "Development of Tools for T Cell Repertoire Analysis (TCRB Spectratyping) for the Canine Model of Hematopoietic Cell Transplantation." Blood 110, no. 11 (November 16, 2007): 4873. http://dx.doi.org/10.1182/blood.v110.11.4873.4873.

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Abstract Analysis of the recombinatorial diversity of rearranged T cell receptor genes in mature T cells is an essential tool in the evaluation of immune status and immune reconstitution in hematopoietic cell transplantation studies. While the spectratyping technique is available in human clinical research and mouse models, the canine genome has not been sufficiently annotated to simply implement the assay on the dog TCRB locus. To this end, we have annotated by bioinformatics and experimentally all canine TCRBV segments, as well as TCRBD, TCRBC and most of TCRBJ segments. Of all 31 canine TCRBV found, 23 were functional and 8 were pseudogenes. A multiplex PCR-based assay was further designed to analyze the entire TCRBV spectratype in a set of 4 reactions each containing 4 to 5 V-segment specific forward primers and a common C-segment specific reverse primer. Direct sequencing of RT-PCR products confirmed that all amplified genes originated from predicted V-segments and that the designed V-specific PCR primers did not cross-react with other TCRBV family members. The usefulness of the spectratyping technique for canine model of transplantation was further demonstrated in analysis of T-cell repertoire reconstitution of irradiated dogs at different time points of recovery. Moreover, our simple and rapid V (J) annotation strategy relies on internet resources open to the general public and does not require specialized training in bioinformatics. It can be readily applied for de novo identification and mapping of TCRB gene families in other animal species where genome sequence drafts become available. Figure 1. TCRB spectratype of fetal canine thymus. (A) RT-PCR using TCRBV family-specific forward primers (V1 through V26) and a common C region-specific reverse primer. (B) Amplification products specific for family V1 (high abundance) and V26 (low abundance) were copied in run-off reactions with the fluorescent C-specific primer and resolved on capillary gel. Figure 1. TCRB spectratype of fetal canine thymus. (A) RT-PCR using TCRBV family-specific forward primers (V1 through V26) and a common C region-specific reverse primer. (B) Amplification products specific for family V1 (high abundance) and V26 (low abundance) were copied in run-off reactions with the fluorescent C-specific primer and resolved on capillary gel.

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Sottini, A., E. Quiros-Roldan, LD Notarangelo, A. Malagoli, D. Primi, and L. Imberti. "Engrafted maternal T cells in a severe combined immunodeficiency patient express T-cell receptor variable beta segments characterized by a restricted V-D-J junctional diversity." Blood 85, no. 8 (April 15, 1995): 2105–13. http://dx.doi.org/10.1182/blood.v85.8.2105.bloodjournal8582105.

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To better understand the peculiar functional behavior of engrafted maternal T cells in a severe combined immunodeficiency (SCID) patient, we characterized, at the molecular level, the T-cell repertoire of a SCID child with a high number of engrafted, mature, activated lymphocytes. We found that, although these transplacentally acquired T cells express a random set of T-cell receptor variable beta (TCRBV) segments, the TCRBV transcripts are characterized by an extremely restricted V-D-J junctional diversity. Only a few cDNA clones were dominant among the TCRBV4+, TCRBV6+, and TCRBV20+ populations in engrafted cells, whereas the same TCRBV chains expressed by the mother's lymphocytes had the expected junctional hetero-geneity. Highly diverse and polyclonal junctions were also expressed by maternal cells activated in mixed lymphocyte reaction by Epstein-Barr virus (EBV)- transformed B lymphocytes from the patient, indicating that the strong clonal selection that characterizes the engrafted cells repertoire is probably not due to allorecognition. Furthermore, we report that the repertoire of the transplacentally acquired lymphocytes is dynamic over time and is characterized by waves of expression and contraction of selected clones, expressing different TCRBV segments. These results help to explain some of the abnormal functional behaviors of engrafted maternal cells and raise new questions regarding the mechanisms responsible for the restricted clonal diversity.

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Schneider-Hohendorf, Tilman, Dennis Görlich, Paula Savola, Tiina Kelkka, Satu Mustjoki, Catharina C. Gross, Geoffrey C. Owens, et al. "Sex bias in MHC I-associated shaping of the adaptive immune system." Proceedings of the National Academy of Sciences 115, no. 9 (February 12, 2018): 2168–73. http://dx.doi.org/10.1073/pnas.1716146115.

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HLA associations, T cell receptor (TCR) repertoire bias, and sex bias have independently been shown for many diseases. While some immunological differences between the sexes have been described, they do not fully explain bias in men toward many infections/cancers, and toward women in autoimmunity. Next-generation TCR variable beta chain (TCRBV) immunosequencing of 824 individuals was evaluated in a multiparametric analysis including HLA-A -B/MHC class I background, TCRBV usage, sex, age, ethnicity, and TCRBV selection/expansion dynamics. We found that HLA-associated shaping of TCRBV usage differed between the sexes. Furthermore, certain TCRBVs were selected and expanded in unison. Correlations between these TCRBV relationships and biochemical similarities in HLA-binding positions were different in CD8 T cells of patients with autoimmune diseases (multiple sclerosis and rheumatoid arthritis) compared with healthy controls. Within patients, men showed higher TCRBV relationship Spearman’s rhos in relation to HLA-binding position similarities compared with women. In line with this, CD8 T cells of men with autoimmune diseases also showed higher degrees of TCRBV perturbation compared with women. Concerted selection and expansion of CD8 T cells in patients with autoimmune diseases, but especially in men, appears to be less dependent on high HLA-binding similarity than in CD4 T cells. These findings are consistent with studies attributing autoimmunity to processes of epitope spreading and expansion of low-avidity T cell clones and may have further implications for the interpretation of pathogenic mechanisms of infectious and autoimmune diseases with known HLA associations. Reanalysis of some HLA association studies, separating the data by sex, could be informative.

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Moss, P., G. Gillespie, P. Frodsham, J. Bell, and H. Reyburn. "Clonal populations of CD4+ and CD8+ T cells in patients with multiple myeloma and paraproteinemia." Blood 87, no. 8 (April 15, 1996): 3297–306. http://dx.doi.org/10.1182/blood.v87.8.3297.bloodjournal8783297.

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Patients with paraproteinemia have abnormalities in their T-cell subsets including inversion of the CD4:CD8 ratio and increased expression of activation markers. Recently, distortions in T-cell receptor (TCR) TCRAV and TCRBV gene segment expression have been reported, although the significance of these observations is unclear given the finding of clonal populations of CD8+ T cells in healthy elderly individuals. We have used an extensive range of TCR V-region- specific monoclonal antibodies to assess TCRAV and TCRBV expression in patients with myeloma and paraproteinemia. TCR sequence analysis was used to assess the clonality of expansions and 3-color fluorescence- activated cell sorting analysis determined the phenotype of the expanded populations. The patients show novel oligoclonal expansions within the CD4+ subset and show an increased frequency of CD8+ expansions. Oligoclonal CD4+ T cells belong to the rare CD4+CD28- T- cell subset, a phenotype associated with granular morphology. CD45RA and CD11b are expressed on many of the CD8 T-cell expansions. Comparison of T-cell receptor sequences from two T-cell clones in one patient suggests a possible role for a common peptide antigen in the generation of the expansions. Further work is needed to identify the relevance of such T cells to the B-cell proliferation.

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Cabaniols, Jean-Pierre, Nicolas Fazilleau, Armanda Casrouge, Philippe Kourilsky, and Jean M. Kanellopoulos. "Most α/β T Cell Receptor Diversity Is Due to Terminal Deoxynucleotidyl Transferase." Journal of Experimental Medicine 194, no. 9 (November 5, 2001): 1385–90. http://dx.doi.org/10.1084/jem.194.9.1385.

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The contribution of template-independent nucleotide addition to antigen receptor diversity is unknown. We therefore determined the size of the T cell receptor (TCR)α/β repertoire in mice bearing a null mutation on both alleles of the terminal deoxynucleotidyl transferase (Tdt) gene. We used a method based upon polymerase chain reaction amplification and exhaustive sequencing of various AV-AJ and BV-BJ combinations. In both wild-type and Tdt°/° mice, TCRAV diversity is one order of magnitude lower than the TCRBV diversity. In Tdt°/° animals, TCRBV chain diversity is reduced 10-fold compared with wild-type mice. In addition, in Tdt°/° mice, one BV chain can associate with three to four AV chains as in wild-type mice. The α/β repertoire size in Tdt°/° mice is estimated to be 105 distinct receptors, ∼5–10% of that calculated for wild-type mice. Thus, while Tdt activity is not involved in the combinatorial diversity resulting from α/β pairing, it contributes to at least 90% of TCRα/β diversity.

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Viëtor, Henk E., Gail E. Hawes, Claudia van den Oever, Els van Beelen, Humphrey H. H. Kanhai, Anneke Brand, and Peter J. Van den Elsen. "Intrauterine Transfusions Affect Fetal T-Cell Immunity." Blood 90, no. 6 (September 15, 1997): 2492–501. http://dx.doi.org/10.1182/blood.v90.6.2492.

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Abstract Intrauterine transfusion (IUT) therapy is the treatment of choice in severe hemolytic disease of the fetus. This treatment automatically implies the introduction of alloantigens in the fetal circulation, which might potentially influence the unprimed fetal immune system. The present study provides evidence that the fetal immune system is indeed prone to modulations of the T-cell receptor BV (TCRBV) repertoire as a result of IUT treatment. Most notably, IUT therapy affects the composition of the CD4+ repertoire, whereas this effect may be obscured in the CD8+ subset. The CD8+ subset was found to be influenced by alterations of the TCRBV repertoire both in IUT patients and controls, suggesting that modulations in this subset could be the result of developmental influences. A more detailed analysis on the composition of the individual TCRBV families was performed by evaluating the distribution of the complementarity determining region 3 (CDR3) size lengths of [32P]-radiolabeled TCRBV transcripts. Using this technique, referred to as spectratyping, only marginal changes were observed in the CD4+ and CD8+ subset during the course of treatment and gestational development of both IUT-treated patients and controls. Therefore, the alterations in the overall TCRBV repertoire were of a quantitative rather than a qualitative nature. To evaluate whether the observed alterations in TCRBV usage-frequencies were a reflection of an allo-reactive response, a primed lymphocyte test (PLT) was performed in 3 IUT-treated patients. We observed that IUT, performed as early as 23 weeks of gestation, may induce the establishment of memory T cells against the IUT donor. However, there was no association between the observed changes in TCRBV repertoire and the magnitude of the secondary allo-reactive response.

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8

Viëtor, Henk E., Gail E. Hawes, Claudia van den Oever, Els van Beelen, Humphrey H. H. Kanhai, Anneke Brand, and Peter J. Van den Elsen. "Intrauterine Transfusions Affect Fetal T-Cell Immunity." Blood 90, no. 6 (September 15, 1997): 2492–501. http://dx.doi.org/10.1182/blood.v90.6.2492.2492_2492_2501.

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Intrauterine transfusion (IUT) therapy is the treatment of choice in severe hemolytic disease of the fetus. This treatment automatically implies the introduction of alloantigens in the fetal circulation, which might potentially influence the unprimed fetal immune system. The present study provides evidence that the fetal immune system is indeed prone to modulations of the T-cell receptor BV (TCRBV) repertoire as a result of IUT treatment. Most notably, IUT therapy affects the composition of the CD4+ repertoire, whereas this effect may be obscured in the CD8+ subset. The CD8+ subset was found to be influenced by alterations of the TCRBV repertoire both in IUT patients and controls, suggesting that modulations in this subset could be the result of developmental influences. A more detailed analysis on the composition of the individual TCRBV families was performed by evaluating the distribution of the complementarity determining region 3 (CDR3) size lengths of [32P]-radiolabeled TCRBV transcripts. Using this technique, referred to as spectratyping, only marginal changes were observed in the CD4+ and CD8+ subset during the course of treatment and gestational development of both IUT-treated patients and controls. Therefore, the alterations in the overall TCRBV repertoire were of a quantitative rather than a qualitative nature. To evaluate whether the observed alterations in TCRBV usage-frequencies were a reflection of an allo-reactive response, a primed lymphocyte test (PLT) was performed in 3 IUT-treated patients. We observed that IUT, performed as early as 23 weeks of gestation, may induce the establishment of memory T cells against the IUT donor. However, there was no association between the observed changes in TCRBV repertoire and the magnitude of the secondary allo-reactive response.

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9

Kluin-Nelemans, Hanneke C., Michel G. D. Kester, Lisette van deCorput, Patrick P. C. Boor, Jim E. Landegent, Jacques J. M. van Dongen, Roel Willemze, and J. H. Frederik Falkenburg. "Correction of Abnormal T-Cell Receptor Repertoire During Interferon-α Therapy in Patients With Hairy Cell Leukemia." Blood 91, no. 11 (June 1, 1998): 4224–31. http://dx.doi.org/10.1182/blood.v91.11.4224.

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Abstract Patients with the B-cell malignancy hairy cell leukemia (HCL) exhibit a skewed T-cell repertoire with oligoclonal expression or absence of many members of the T-cell receptor (TCR) BV gene families. To evaluate whether interferon-α (IFN-α) therapy would not only restore normal hematopoiesis, but also the abnormal T-cell repertoire, we studied T lymphocytes from a cohort of HCL patients treated by IFN-α in the past, at initiation, and at several intervals up to 6 years of IFN-α treatment. The junctional regions from 22 TCRBV gene families were analyzed after polymerase chain reaction amplification of cDNA (RT-PCR) using family specific primers. In all seven patients improvement of the skewed T-cell repertoire was not seen until 2 years of treatment. It consisted of disappearance of oligoclonal subpopulations and (polyclonal) reappearance of absent TCRBV gene families. The RT-PCR results were correlated with the TCRBV protein expression using TCRBV-specific monoclonal antibodies. T lymphocytes from four patients with active HCL contained large expansions of particular TCRBV-expressing cells (up to 25% of the CD3+cells; 600 to 700/μL whole blood), which decreased during IFN-α therapy in both patients tested. Finally, restoration of the TCR repertoire matched normalization of the functional immune repertoire as measured by proliferative, helper, and cytotoxic T-lymphocyte precursor frequencies against major histocompatibility complex–unrelated individuals. In conclusion, oligoclonal bands of TCRBV gene families found by RT-PCR correspond with a dramatic increase in circulating T lymphocytes expressing the same TCRBV family. Moreover, IFN-α can restore the skewed T-cell repertoire and suppress persistent T-cell clones upon treatment of the accompanying malignancy.

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10

Kluin-Nelemans, Hanneke C., Michel G. D. Kester, Lisette van deCorput, Patrick P. C. Boor, Jim E. Landegent, Jacques J. M. van Dongen, Roel Willemze, and J. H. Frederik Falkenburg. "Correction of Abnormal T-Cell Receptor Repertoire During Interferon-α Therapy in Patients With Hairy Cell Leukemia." Blood 91, no. 11 (June 1, 1998): 4224–31. http://dx.doi.org/10.1182/blood.v91.11.4224.411k19_4224_4231.

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Patients with the B-cell malignancy hairy cell leukemia (HCL) exhibit a skewed T-cell repertoire with oligoclonal expression or absence of many members of the T-cell receptor (TCR) BV gene families. To evaluate whether interferon-α (IFN-α) therapy would not only restore normal hematopoiesis, but also the abnormal T-cell repertoire, we studied T lymphocytes from a cohort of HCL patients treated by IFN-α in the past, at initiation, and at several intervals up to 6 years of IFN-α treatment. The junctional regions from 22 TCRBV gene families were analyzed after polymerase chain reaction amplification of cDNA (RT-PCR) using family specific primers. In all seven patients improvement of the skewed T-cell repertoire was not seen until 2 years of treatment. It consisted of disappearance of oligoclonal subpopulations and (polyclonal) reappearance of absent TCRBV gene families. The RT-PCR results were correlated with the TCRBV protein expression using TCRBV-specific monoclonal antibodies. T lymphocytes from four patients with active HCL contained large expansions of particular TCRBV-expressing cells (up to 25% of the CD3+cells; 600 to 700/μL whole blood), which decreased during IFN-α therapy in both patients tested. Finally, restoration of the TCR repertoire matched normalization of the functional immune repertoire as measured by proliferative, helper, and cytotoxic T-lymphocyte precursor frequencies against major histocompatibility complex–unrelated individuals. In conclusion, oligoclonal bands of TCRBV gene families found by RT-PCR correspond with a dramatic increase in circulating T lymphocytes expressing the same TCRBV family. Moreover, IFN-α can restore the skewed T-cell repertoire and suppress persistent T-cell clones upon treatment of the accompanying malignancy.

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11

Melenhorst, J. Joseph, Josette Zeilah, Edgardo Sosa, Dean Follmann, Nancy F. Hensel, and Austin J. Barrett. "Analysis of the Human T Cell Receptor (TCR) Repertoire from Birth to Old Age Suggests That TCRVβfrequencies Are Established Independent of HLA." Blood 106, no. 11 (November 16, 2005): 3313. http://dx.doi.org/10.1182/blood.v106.11.3313.3313.

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Abstract Human T cell development occurs in two waves of development and proliferation: first, early T cells expressing the TCRb chain but not the α-chain are selected for functional TCRβ protein independent of HLA recognition, a process called β-selection; second, thymocytes expressing both the α- and β-TCR are selected for intermediate affinity for self-MHC/ self-peptide complex. This latter process is referred to as positive selection. We sought to determine whether the peripheral TCRVβ frequencies in the naïve T cell repertoire start off at a fixed rank order with minimal skewing as would be expected from a predominantly β-selected repertoire. A total of 22 TCRVβ proteins was quantitated by flow cytometry in a group of 20 unselected umbilical cord blood (UCB) samples (a kind gift from Dr. P. Rubinstein, NY Blood Center, NY), consisting of >80% naïve T cells as defined by CD27+CD45RA+ staining in CD4+ and CD8+ cells. A common rank order of TCRVβ protein frequencies was found in both CD4 and CD8 T cell subsets (figure 1). Median TCRVβ frequencies in CD4 and in CD8 cells of UCB were statistically not significantly different from the frequencies in adult donor CD4 and CD8 cells (Wilcoxon signed rank test; p > 0.2). Furthermore, the percentages of CD4 cells expressing a particular Vβ correlated significantly in CD8 cells (figure 2) with some Vβ proteins being predominantly expressed by either CD4 (Vβ2, Vβ5.1) or CD8 (Vβ14, Vβ7) cells. Our data therefore conform to the prediction that the TCRVβ frequencies are dominantly shaped by β-selection, and not by interactions of the αβTCR/ co-receptor with MHC/ antigen complexes during thymic selection. Figure 1. TCRBV in UCB CD4+ (top) and CD8+ (bottom) T cells Figure 1. TCRBV in UCB CD4+ (top) and CD8+ (bottom) T cells Figure 2. Comparison of TCRBV protein expression frequencies in CD4 and CD8 cells of UCB Figure 2. Comparison of TCRBV protein expression frequencies in CD4 and CD8 cells of UCB

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Matsutani, Takaji, Takeshi Yoshioka, Yuji Tsuruta, Shoji Iwagami, and Ryuji Suzuki. "Analysis of TCRAV and TCRBV Repertoires in Healthy Individuals by Microplate Hybridization Assay." Human Immunology 56, no. 1-2 (August 1997): 57–69. http://dx.doi.org/10.1016/s0198-8859(97)00102-x.

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13

Saubermann, Lawrence J., Christopher S. J. Probert, Andreas D. Christ, Andreas Chott, Jerrold R. Turner, A. Christopher Stevens, Steven P. Balk, and Richard S. Blumberg. "Evidence of T cell receptor β-chain patterns in inflammatory and noninflammatory bowel disease states." American Journal of Physiology-Gastrointestinal and Liver Physiology 276, no. 3 (March 1, 1999): G613—G621. http://dx.doi.org/10.1152/ajpgi.1999.276.3.g613.

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T cell activation, as defined by expression of relevant cell surface molecules, such as the interleukin-2 receptor (CD25), is increased in many chronic relapsing diseases, including inflammatory bowel disease (IBD). These T cells are generally activated through contact of their clonotypic T cell receptor (TCR) with a peptide antigen presented by a major histocompatibility complex molecule. One of the putative antigenic contact sites for the TCR is the third complementarity determining region (CDR3) of the TCR β-chain variable region (TCRBV). Therefore, analysis of the TCRBV CDR3 provides insight into the diversity of antigens encountered by a given T cell population. This study evaluated the TCRBV CDR3 usage of the activated intestinal lymphocytes from human subjects with IBD, diverticulitis (inflammatory control), and a normal tissue control. Public patterns, as demonstrated by shared TCRBV CDR3 amino acid sequences of activated intestinal T cell subpopulations, were observed. In particular, a public pattern of TCRBV22, a conserved valine in the fifth position, and use of TCRBJ2S1 or TCRBJ2S5 was present in three of four Crohn’s disease subjects while not present in the ulcerative colitis subjects. However, the private patterns of TCRBV CDR3 region amino acid sequences were far more striking and easily demonstrated in all individuals studied, including a normal noninflammatory control. Thus we conclude that selective antigenic pressures are prevalent among an individual’s activated intestinal lymphocytes.

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Raaphorst, Frank M., Jeroen van Bergen, Renée Langlios van den Bergh, Maarten van der Keur, Ronald de Krijger, Jan Bruining, Maarten J. D. van Tol, Jaak M. Vossen, and Peter J. van den Elsen. "Usage of TCRAV and TCRBV gene families in human fetal and adult TCR rearrangements." Immunogenetics 39, no. 5 (March 1994): 343–50. http://dx.doi.org/10.1007/bf00189231.

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15

Soudeyns, Hugo, Gabriele Campi, G. Paolo Rizzardi, Caterina Lenge, James F. Demarest, Giuseppe Tambussi, Adriano Lazzarin, et al. "Initiation of antiretroviral therapy during primary HIV-1 infection induces rapid stabilization of the T-cell receptor β chain repertoire and reduces the level of T-cell oligoclonality." Blood 95, no. 5 (March 1, 2000): 1743–51. http://dx.doi.org/10.1182/blood.v95.5.1743.005k14_1743_1751.

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Major T-cell receptor β chain variable region (TCRBV) repertoire perturbations are temporally associated with the down-regulation of viremia during primary human immunodeficiency virus (HIV) infection and with oligoclonal expansion and clonal exhaustion of HIV-specific cytotoxic T lymphocytes (CTLs). To determine whether initiation of antiretroviral therapy (ART) or highly active antiretroviral therapy (HAART) during primary infection influences the dynamics of T-cell–mediated immune responses, the TCRBV repertoire was analyzed by semiquantitative polymerase chain reaction in serial blood samples obtained from 11 untreated and 11 ART-treated patients. Repertoire variations were evaluated longitudinally. Stabilization of the TCRBV repertoire was more consistently observed in treated as compared with untreated patients. Furthermore, the extent and the rapidity of stabilization were significantly different in treated versus untreated patients. TCRBV repertoire stabilization was positively correlated with the slope of HIV viremia in the treated group, suggesting an association between repertoire stabilization and virologic response to treatment. To test whether stabilization was associated with variations in the clonal complexity of T-cell populations, T-cell receptor (TCR) heteroduplex mobility shift assays (HMAs) were performed on sequential samples from 4 HAART-treated subjects. Densitometric analysis of HMA profiles showed a reduction in the number of TCR clonotypes in most TCRBV families and a significant decrease in the total number of clonotypes following 7 months of HAART. Furthermore, a biphasic decline in HIV-specific but not heterologous CTL clones was observed. This indicates that ART leads to a global reduction of CD8+T-cell oligoclonality and significantly modulates the mobilization of HIV-specific CTL during primary infection.

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Hawes, Gail E., Henk E. Viëtor, Humphrey H. Kanhai, and Peter J. van den Elsen. "TCRBV gene expression patterns are shaped prior to TCRAV gene expression patterns during thymic development." Immunology Letters 56 (May 1997): 90. http://dx.doi.org/10.1016/s0165-2478(97)85351-5.

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Hawes, G. "TCRBV gene expression patterns are shaped prior to TCRAV gene expression patterns during thymic development." Immunology Letters 56, no. 1-3 (May 1997): 90. http://dx.doi.org/10.1016/s0165-2478(97)87189-1.

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Rezvany, Mohammad-Reza, Mahmood Jeddi-Tehrani, Anders Österborg, Eva Kimby, Hans Wigzell, and Håkan Mellstedt. "Oligoclonal TCRBV Gene Usage in B-Cell Chronic Lymphocytic Leukemia: Major Perturbations Are Preferentially Seen Within the CD4 T-Cell Subset." Blood 94, no. 3 (August 1, 1999): 1063–69. http://dx.doi.org/10.1182/blood.v94.3.1063.415a17_1063_1069.

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TCRBV (T-cell receptor B variable) gene usage and CDR3 size distribution were analyzed using reverse transcription polymerase chain reaction (RT-PCR) to assess the T-cell repertoire of 10 patients with B-cell chronic lymphocytic leukemia (B-CLL) and in nine age-matched healthy control donors. When the usage of each TCRBV gene within the CD8+ T cells of the patients was compared with that of the controls, no statistically significant difference was noted except for BV 6S1-3. In contrast, within the CD4+ T cells of the CLL patients, a statistically significant overexpression for four BV families (2, 3, 5S1, 6S1-3) was seen while an underrepresentation was noted for five BV families (10, 11, 15, 16, 19). Based on the criterion that a value of any BV higher than the mean + 3 standard deviation (SD) of healthy controls indicated an overexpression, individual patients were shown to overexpress several TCRBV genes compared with the controls. Analyses of the CDR3 length polymorphism showed a significantly higher degree of restriction within CD4+ and CD8+ T cells of the patients, as compared with the corresponding control T-cell population. There was a significant difference in the CDR3 size distribution pattern with a more polymorphic CDR3 length pattern in the age-matched controls as compared with CLL patients, suggesting different mechanisms driving the T cells towards a clonal/oligoclonal TCRBV usage in patients and controls, respectively. The results show major perturbations of T cells in CLL patients, more frequently seen in the CD4+ T-cell subset, indicating that nonmalignant CD4+ T cells may be involved in the pathogenesis of CLL, but also CD8+ T cells.

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Fu, Yue Wen, De Pei Wu, Feng Chen, Yu Feng Feng, Wei Rong Chong, Zi Ling Zhu, and Ping Zhu. "Organ-Specific T Cell Receptor Repertoire in Target Organs of Murine Graft-Versus-Host after Haploidentical Bone Marrow Transplantation." Blood 110, no. 11 (November 16, 2007): 4859. http://dx.doi.org/10.1182/blood.v110.11.4859.4859.

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Abstract Objective Haploidentical bone marrow transplantation (Haploidentical-BMT) usually has high morbidity and mortality associated with the early complication of SCT and severe GVHD. GVHD-associated T-cell clones can be identified in GVHD-affected tissues. In our study, Murine CB6F1(H-2b/d, [male]) and C57BL/6(H-2b, [female]) haploidentical-BMT GVHD model was established and proved a novel method to study the characteristics of T cell receptor repertoire in target organs of murine GVHD and research the molecular characteristics of T cell receptor BV complementarity determining region3 (TCRBV CDR3) repertoires of these monoclonal T cells in liver, skin and ileum. Methods Murine haploidentical BMT model was established, RT-PCR was used to amplify 24 subfamily genes of TCRBV from liver, skin, ileum, spleen and kidney, PCR products were further analyzed by genescan to evaluate the clonality of BV subfamily and characteristics of CDR3, monoclonal bands were obtained thorough denaturation polyacrylamide gel electrophoresis and sequenced. A group of CDR3 molecules were obtained from GVHD-target tissues. Results GVHD occurred as early as days 14 and was proven by histology in liver, skin and ileum. After BMT, it emerged a number of new monoclonal and oligoclonal T cells in GVHD-target tissues, while kidney was not affected by GVHD and infiltrated by polycolnal T cell. 48 TCRBV CDR3 molecules of monoclonal T cells which obtained from liver, skin, ileum in different times after BMT have six C’-terminal motifs(TEVFF, DTQYF, YEQYF, A EQ (Y F/FF), QNTLY F, AE T L Y F)and use restricted JB genes(JB1.1, JB2.5, JB2.7, JB2.1, JB2.4, JB2.3). Conclusion Through murine haploidentical BMT GVHD model, TCRBV CDR3 was detected in GVHD-target tissues (liver, skin, ileum) and found that it emerged a number of monoclonal or oligoclonal T cells which associated with the development of GVHD and existed conserved CDR3 motifs.

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Kluin-Nelemans, JC, MG Kester, JJ Melenhorst, JE Landegent, L. van de Corput, R. Willemze, and JH Falkenburg. "Persistent clonal excess and skewed T-cell repertoire in T cells from patients with hairy cell leukemia." Blood 87, no. 9 (May 1, 1996): 3795–802. http://dx.doi.org/10.1182/blood.v87.9.3795.bloodjournal8793795.

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Hairy cell leukemia (HCL) is characterized by a severe T-cell-mediated immune deficiency. At the same time, spontaneous T-cell activation is noted when splenic T cells are studied in vivo and in vitro. Therefore, we searched for oligoclonal T-cell populations in the blood and spleens of 25 patients with HCL using a T-cell receptor gamma-polymerase chain reaction (TCR gamma-PCR). Subsequently, in 6 patients, the CDR3 length and conformation from 22 different TCRBV subfamilies were analyzed after PCR amplification of cDNA using TCRBV subfamily-specific primers. T cells from 15 of 25 HCL patients showed clonal excess by the TCR gamma-PCR. In fluorescence-activated cell sorted T-cell subsets, more clonal bands were observed than in the unseparated T cells, with most of these in CD8+ subsets, but also in CD4+, CD3+ gamma/delta+, and a double-negative CD3+ alpha/beta+ subset. In other B-cell malignancies, 6 of 16 samples showed oligoclonal T cells, whereas only 2 of 18 normal spleen and blood samples showed abnormal bands. Analysis of the TCRBV subfamilies disclosed in all 6 HCL patients a markedly abnormal pattern, with many clonal bands in 5 to 15 subfamilies, and absent or abnormal weak patterns in another 1 to 8 subfamilies. In comparison, 6 normal samples (2 spleens and 4 blood samples) showed in only 1 blood donor 1 clonal band. Two patients with active HCL but without infections or treatment were tested several times during the course of the disease and showed a complete identical skewed T-cell repertoire with the same oligoclonal T-cell populations. In conclusion, T cells in the blood and spleen of HCL patients show impressive abnormalities with many oligoclonal T-cell populations and a very restricted and skewed TCRBV repertoire.

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Sottini, A., A. Bettinardi, E. Quiros-Roldan, A. Plebani, P. Airo, D. Primi, and L. Imberti. "Evidence for antigenic selection of large granular lymphocytes in a patient with Wiskott-Aldrich syndrome." Blood 86, no. 6 (September 15, 1995): 2240–47. http://dx.doi.org/10.1182/blood.v86.6.2240.bloodjournal8662240.

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It is now recognized that CD3+ large granular lymphocyte (LGL) proliferations may be clonally derived from their normal CD3+LGL+ counterpart, but the nature of the pressure responsible for the proliferation of these cells remains unclear. We approached this problem by analyzing the diversity of the T-cell receptor repertoire of LGL developed in different clinical settings. Two of our patients had typical lymphoproliferative disorders. The third case was much more unusual, as the LGL proliferation was associated with a Wiskott-Aldrich syndrome. Our data relative to the patients with the lymphoproliferative disorders only suggest that these LGL were clonally expanded. The data relative to the patient with Wiskott-Aldrich syndrome were more unexpected, as the T-cell repertoire of the LGL appeared to have common features with that of the other T-cell populations analyzed. These LGL were characterized by the clonal expansion of a few TCRBV segments that shared common amino acid motifs in the junctional region of the T-cell receptor. This common pattern of junctional diversity associated with different TCRBV segments is, therefore, consistent with a strong on-going antigenic selection process, possibly related to the pathogenesis of Wiskott-Aldrich syndrome. Furthermore, the finding that the same TCRBV segments were also highly expanded among other T-cell subpopulations questions the malignant nature of this LGL proliferation.

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Garderet, Laurent, Nicolas Dulphy, Corinne Douay, Nathalie Chalumeau, Véronique Schaeffer, Marie-Thérèse Zilber, Annick Lim, et al. "The Umbilical Cord Blood αβ T-Cell Repertoire: Characteristics of a Polyclonal and Naive but Completely Formed Repertoire." Blood 91, no. 1 (January 1, 1998): 340–46. http://dx.doi.org/10.1182/blood.v91.1.340.

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Abstract Umbilical cord blood (CB) constitutes a promising alternative to bone marrow for allogeneic transplantation and is increasingly used because of the reduced severity of graft-versus-host disease after CB transplantation. We have compared the T-cell receptor β chain (TCRB) diversity of CB lymphocytes with that of adult lymphocytes by analyzing the complementarity determining region 3 (CDR3) size heterogeneity. In marked contrast to adult samples, we observed bell-shaped profiles in all of the 22 functional β-chain variable (BV) subfamilies that reflect the lack of prior antigenic stimulation in CB samples. However, the mean CDR3 size and BV usage were comparable between CB and adult samples. BJ2 (65%) segments were used preferentially to BJ1 (35%), especially BJ2S7, BJ2S5, BJ2S3, and BJ2S1, in both CB and in adult lymphocytes. We therefore conclude that although naive as reflected by the heterogeneity of the CDR3 size, the TCRBV repertoire appears fully constituted at birth. The ability to expand TCRB subfamilies was confirmed by stimulation with staphylococcal superantigens toxic shock syndrome toxin-1 and staphylococcal enterotoxin A. This study provides the basis for future analysis of the T-cell repertoire reconstitution following umbilical CB transplantation.

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Garderet, Laurent, Nicolas Dulphy, Corinne Douay, Nathalie Chalumeau, Véronique Schaeffer, Marie-Thérèse Zilber, Annick Lim, et al. "The Umbilical Cord Blood αβ T-Cell Repertoire: Characteristics of a Polyclonal and Naive but Completely Formed Repertoire." Blood 91, no. 1 (January 1, 1998): 340–46. http://dx.doi.org/10.1182/blood.v91.1.340.340_340_346.

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Umbilical cord blood (CB) constitutes a promising alternative to bone marrow for allogeneic transplantation and is increasingly used because of the reduced severity of graft-versus-host disease after CB transplantation. We have compared the T-cell receptor β chain (TCRB) diversity of CB lymphocytes with that of adult lymphocytes by analyzing the complementarity determining region 3 (CDR3) size heterogeneity. In marked contrast to adult samples, we observed bell-shaped profiles in all of the 22 functional β-chain variable (BV) subfamilies that reflect the lack of prior antigenic stimulation in CB samples. However, the mean CDR3 size and BV usage were comparable between CB and adult samples. BJ2 (65%) segments were used preferentially to BJ1 (35%), especially BJ2S7, BJ2S5, BJ2S3, and BJ2S1, in both CB and in adult lymphocytes. We therefore conclude that although naive as reflected by the heterogeneity of the CDR3 size, the TCRBV repertoire appears fully constituted at birth. The ability to expand TCRB subfamilies was confirmed by stimulation with staphylococcal superantigens toxic shock syndrome toxin-1 and staphylococcal enterotoxin A. This study provides the basis for future analysis of the T-cell repertoire reconstitution following umbilical CB transplantation.

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24

Brugnoni, D., P. Airo, G. Rossi, A. Bettinardi, HU Simon, L. Garza, C. Tosoni, R. Cattaneo, K. Blaser, and A. Tucci. "A case of hypereosinophilic syndrome is associated with the expansion of a CD3-CD4+ T-cell population able to secrete large amounts of interleukin-5." Blood 87, no. 4 (February 15, 1996): 1416–22. http://dx.doi.org/10.1182/blood.v87.4.1416.bloodjournal8741416.

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Interleukin-5 (IL-5) is the major soluble factor able to mediate hypereosinophilia. We report a case of hypereosinophilic syndrome in which the presence of a population of CD3-CD4+ cells able to overproduce IL-5 was shown. The lack of CD3 and TCRAB membrane expression on otherwise phenotypically normal mature T lymphocytes together with the absence of detectable TCRBV mRNA and clonal rearrangement of TCRB gene suggested that the abnormal lymphocyte population was the expression of a peripheral T-cell lymphoma with an indolent clinical course. Peripheral blood lymphocytes enriched in this population were able to secrete high levels of IL-5 but not IL-4, and no IL-2 or interferon-gamma, when stimulated in vitro with phytohemagglutinin and phorbol myristate acetate. The serum contained eosinophil survival factors whose activity was partially neutralized by a specific antihuman IL-5 antibody. This observation further emphasized the relationship between hypereosinophilic syndrome. IL-5, and T-cell lymphoproliferative disorders.

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Peggs, Karl, Stephanie Verfuerth, Arnold Pizzey, Jenni Ainsworth, Paul Moss, and Stephen Mackinnon. "Characterization of human cytomegalovirus peptide–specific CD8+ T-cell repertoire diversity following in vitro restimulation by antigen-pulsed dendritic cells." Blood 99, no. 1 (January 1, 2002): 213–23. http://dx.doi.org/10.1182/blood.v99.1.213.

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Under conditions of impaired T-cell immunity, human cytomegalovirus (HCMV) can reactivate from lifelong latency, resulting in potentially fatal disease. A crucial role for CD8+ T cells has been demonstrated in control of viral replication, and high levels of HCMV-specific cytotoxic T-lymphocytes are seen in immunocompetent HCMV-seropositive individuals despite very low viral loads. Elucidation of the minimum portion of the anti-HCMV T-cell repertoire that is required to suppress viral replication requires further study of clonal composition. The ability of dendritic cells to take up and process exogenous viral antigen by constitutive macropinocytosis was used to study HCMV-specific T-cell memory in the absence of viral replication. The specificity and clonal composition of the CD8+ T-cell responses were evaluated using HLA tetrameric complexes and T-cell receptor β chain (TCRBV) spectratypic analyses. There was a skewed reactivity toward the matrix protein pp65, with up to 40-fold expansion of CD8+ T cells directed toward a single peptide-MHC combination. Individual expansions detected on TCRBV spectratype analysis were HCMV-specific and composed of single or highly restricted numbers of clones. There was preferential TCRBV gene usage (BV6.1/6.2, BV8, and BV13 in HLA-A*0201+ individuals) but lack of conservation of CDR3 length and junctional motifs between donors. While there was a spectrum of TCR repertoire diversity directed toward individual MHC-peptide combinations between donors, a relatively small number of clones appeared to predominate the response in each case. These data provide further insight into the range of anti-HCMV responses and will aid the design and monitoring of adoptive immunotherapy protocols.

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Houston, E. F., and W. I. Morrison. "Identification of seven new TCRBV subfamilies in cattle (Bos taurus )*." European Journal of Immunogenetics 26, no. 5 (October 1999): 349–53. http://dx.doi.org/10.1046/j.1365-2370.1999.00169.x.

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27

Uhrberg, Markus, and Peter Wernet. "Quantitative assessment of the human TCRBV repertoire by competitive PCR." Journal of Immunological Methods 194, no. 2 (August 1996): 155–68. http://dx.doi.org/10.1016/0022-1759(96)00082-8.

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28

Yassai, Maryam B., Wendy Demos, and Jack Gorski. "Structural and Mechanistic Implications of Rearrangement Frequencies within Human TCRBV Genes." Journal of Immunology 199, no. 3 (June 28, 2017): 1142–52. http://dx.doi.org/10.4049/jimmunol.1601450.

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29

Sartono, E. "Selective usage of defined TCRBV genes in response to filarial antigens." International Immunology 9, no. 7 (July 1, 1997): 955–62. http://dx.doi.org/10.1093/intimm/9.7.955.

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30

Obata, Fumiya, Misao Tsunoda, Takehisa Kaneko, Koichi Ito, Ichiro Ito, Susan Masewicz, EricM Mickelson, et al. "Human T-cell receptor TCRAV, TCRBV, and TCRAJ sequences newly found in T-cell clones reactive with allogeneic HLA class II antigens." Immunogenetics 38, no. 1 (March 1993): 67–70. http://dx.doi.org/10.1007/bf00216395.

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31

Fraser, P. A., L.-Y. Lu, K. DeCeulaer, P. H. Schur, D. Fici, Z. Awdeh, W.-Z. Ding, et al. "CD4 TCRBV CDR3 Analysis in prevalent SLE Cases from two ethnic Groups." Lupus 8, no. 4 (May 1999): 311–19. http://dx.doi.org/10.1191/096120399678847902.

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32

Quiros-Roldan, E., A. Sottini, M. Gulletta, R. Stellini, M. Puoti, D. Primi, and L. Imberti. "The T-cell receptor repertoires expressed by CD4+ and CD4- large granular lymphocytes derived from the same patients suggest the persistent action of an immune-mediated selection process." Blood 88, no. 6 (September 15, 1996): 2133–43. http://dx.doi.org/10.1182/blood.v88.6.2133.bloodjournal8862133.

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The lymphoproliferative syndrome with large granular lymphocytes (LGL) is an heterogeneous disorder of unknown etiology. The analysis of T- cell receptor (TCR) genes rearrangements has shown that, in most cases, the disease is associated with clonal proliferation of CD8+CD57+ LGL. However, the putative neoplastic nature of these expansions remains questionable because clonal proliferations of CD8+ cells have recently been found also in physiologic conditions. To obtain more precise information on the mechanisms responsible for LGL expansions, we decided to compare the molecular characteristics of TCRBV chains expressed by LGL with different phenotype and function, but derived from the same patients. To this end, we characterized, at the molecular level, the TCR repertoires of fractionated T-cell populations of two unusual patients with concurrent expansions of CD4+CD57+ and CD4-CD57+ LGL. Our results show that the dominant TCRBV chains expressed by the different CD4+ and CD4- LGL populations were strictly oligoclonal. However, the molecular characteristics of the dominant V-D-J rearrangements also imply that the selection of these clones was not due to a neoplastic event. Rather, our data suggest that these particular LGL proliferations can be ascribed to a chronic T-cell- mediated immune response that involves recognition by the engaged TCR of antigens that are not necessarily presented to immune system in the classical major histocompatibility complex-restricted pathway.

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Hirokawa, M., T. Matsutani, H. Saitoh, Y. Ichikawa, Y. Kawabata, T. Horiuchi, A. Kitabayashi, et al. "Distinct TCRAV and TCRBV repertoire and CDR3 sequence of T lymphocytes clonally expanded in blood and GVHD lesions after human allogeneic bone marrow transplantation." Bone Marrow Transplantation 30, no. 12 (December 2002): 915–23. http://dx.doi.org/10.1038/sj.bmt.1703730.

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34

Le, Robert Q., J. Joseph Melenhorst, Brenna Hill, Sarfraz Memon, Minoo Battiwalla, Bipin N. Savani, Aarthi Shenoy, et al. "Evolution of the Donor T Cell Repertoire In Allogeneic Stem Cell Transplant Recipients In the Second Decade After Transplantation." Blood 116, no. 21 (November 19, 2010): 831. http://dx.doi.org/10.1182/blood.v116.21.831.831.

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Abstract Abstract 831 After allogeneic stem cell transplantation (SCT), donor T lymphocyte immune function is slowly re-established in the recipient through reconstruction of the donor's post-thymic T cell repertoire and from T cell neogenesis in the thymus. Although long-term survivors from SCT appear healthy, their immune repertoire and differences from that of their donors have not been characterized. We studied 38 healthy patients surviving more than 10 years from a myeloablative SCT for hematological malignancy (median follow-up 12 years, range 10–16 years). T cell and natural killer (NK) cell repertoires in these patients were compared with cells from their stem cell donors cryopreserved at time of transplant and from the same donors at 10 year after SCT. The median age of both recipients and their sibling donors at time of transplant was identical (36 years). Patients received cyclosporine GVHD prophylaxis and delayed add-back of donor lymphocytes 30–90 days post transplant. Only one patient was on continued immunosuppressive treatment at the time of study. Compared with the donor pre-transplant counts there was no significant difference in the absolute lymphocyte, neutrophil, monocyte, CD4+ and CD8+ T cell, NK cell, and B cell subset counts. However, compared to their donors, recipients had a) significantly fewer naïve CD4+ and CD8+ T cells; b) lower T cell receptor excision circles levels; c) fewer CD4+ central memory T cells; d) more effector CD8+ T cells; e) and more FOXP3+ regulatory T cells. These data suggest that the patient had a persistent deficiency on T cell neogenesis. Molecular examination of the T cell receptor Vbeta (TCRBV) repertoire by spectratype analysis showed that there was no significant difference in total complexity score, defined as the sum of the number of discrete peaks for each Vbeta subfamily, between the patients and their donors. TCRBV subfamily spectratyping profiles of patients and donors, however, had diverged, with both gains and losses of peaks identifiable in both patient and donor. In conclusion, patients surviving 10 or more years after allogeneic SCT still show a T cell repertoire that reflects expansion of the donor-derived post thymic T cell compartment, with a limited contribution by new T cell generation and persistently increased Tregs. It therefore appears that a diverse TCRBV repertoire predominantly derived from the memory T cell pool is compatible with good health. Disclosures: No relevant conflicts of interest to declare.

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35

Raaphorst, Frank M., Robert L. Schelonka, Janice Rusnak, Anthony J. Infante, and Judy M. Teale. "TCRBV CDR3 diversity of cd4+ and cd8+ t-lymphocytes in HIV-infected individuals." Human Immunology 63, no. 1 (January 2002): 51–60. http://dx.doi.org/10.1016/s0198-8859(01)00361-5.

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36

Sheih, Alyssa, Laila-Aicha Hanafi, Valentin Voillet, Hannah A. DeBerg, Reed M. Hawkins, Masanao Yajima, Vivian Gersuk, Peter S. Linsley, Raphael Gottardo, and Cameron J. Turtle. "Clonal Kinetics and Single Cell Transcriptional Profiling of Adoptively Transferred CD19 CAR-T Cells." Blood 132, Supplement 1 (November 29, 2018): 702. http://dx.doi.org/10.1182/blood-2018-99-111350.

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Abstract INTRODUCTION: When introduced into polyclonal T cells, chimeric antigen receptors (CAR) redirect specificity of the engineered T cells to an antigen recognized by the CAR. We conducted a phase I/II clinical trial of treatment of relapsed and refractory CD19-positive B cell malignancies using a defined formulation of CD4+ and CD8+ CD19-specific CAR-T cells (NCT01865617). Little is known about the transcriptional heterogeneity of CAR-T cells in the infused product and their clonal kinetics after adoptive transfer. METHODS: To understand the factors that impact clonal CAR-T cell behavior in vivo, we performed TCRBV sequencing and single cell transcriptional profiling (10X Genomics) on CD8+ CAR-T cells isolated from infused products and the blood of treated patients. TCRBV sequencing was performed on 0.8 to 1.5 million cells from the infused product and 700-65,000 CAR-T cells from blood after CAR-T infusion. For single-cell RNA sequencing (scRNAseq), we obtained paired 5' gene expression and V(D)J data from individual CAR-T cells isolated from infused products and from the blood at the peak of in vivo expansion, after contraction, and at a late time point. RESULTS: High-throughput sequencing of the TCRBV genes revealed that CAR-T cells were polyclonal in the infused products, and during in vivo expansion and contraction, and at late times (≥ 3 months) after adoptive transfer. We evaluated the diversity of the TCRBV repertoire using the Shannon entropy index, and found that clonal diversity was highest in the infused product and declined at later time points after adoptive transfer. Loss of diversity after adoptive transfer was due to both expansion of higher frequency CAR-T cell clones and loss of low-frequency clones. We identified distinct CAR-T cell clones in the infused product and in blood at multiple time points after infusion that exhibited different kinetics of expansion and contraction. To examine the transcriptional programs that regulate the fate of CAR-T cells after infusion, we performed scRNAseq on CD8+ CAR-T cells, and found transcriptional heterogeneity in the infused products, which declined in CD8+ CAR-T cells isolated from patient blood after adoptive transfer. Gene set enrichment analysis showed that the infused products expressed higher levels of genes associated with hypoxia, glycolysis, and proliferation, and lower levels of genes associated with cytotoxicity compared to CAR-T cells isolated after adoptive transfer. In the infused product, genes associated with cytotoxicity were expressed at higher levels in CAR-T cells harboring clonotypes that were subsequently represented at relatively higher levels in vivo after adoptive transfer. CONCLUSIONS: There is transcriptional heterogeneity in the infused product and distinct CAR-T cell clones exhibit different kinetics of expansion and contraction after infusion. A better understanding of the kinetics of clonal expansion of CAR-T cells after adoptive transfer may provide insight into strategies to improve CAR-T cell immunotherapy. Disclosures Turtle: Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Membership on an entity's Board of Directors or advisory committees; Juno/Celgene: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

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37

Markert, M. Louise, Marcella Sarzotti, Daniel A. Ozaki, Gregory D. Sempowski, Maria E. Rhein, Laura P. Hale, Francoise Le Deist, et al. "Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients." Blood 102, no. 3 (August 1, 2003): 1121–30. http://dx.doi.org/10.1182/blood-2002-08-2545.

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Abstract Complete DiGeorge syndrome is a fatal condition in which infants have no detectable thymus function. The optimal treatment for the immune deficiency of complete DiGeorge syndrome has not been determined. Safety and efficacy of thymus transplantation were evaluated in 12 infants with complete DiGeorge syndrome who had less than 20-fold proliferative responses to phytohemagglutinin. All but one had fewer than 50 T cells/mm3. Allogeneic postnatal cultured thymus tissue was transplanted. T-cell development was followed by flow cytometry, lymphocyte proliferation assays, and T-cell receptor Vβ (TCRBV) repertoire evaluation. Of the 12 patients, 7 are at home 15 months to 8.5 years after transplantation. All 7 survivors developed T-cell proliferative responses to mitogens of more than 100 000 counts per minute (cpm). By one year after transplantation, 6 of 7 patients developed antigen-specific proliferative responses. The TCRBV repertoire showed initial oligoclonality that progressed to polyclonality within a year. B-cell function developed in all 3 patients tested after 2 years. Deaths were associated with underlying congenital problems. Risk factors for death included tracheostomy, long-term mechanical ventilation, and cytomegalovirus infection. Adverse events in the first 3 months after transplantation included eosinophilia, rash, lymphadenopathy, development of CD4-CD8- peripheral T cells, elevated serum immunoglobulin E (IgE), and possible pulmonary inflammation. Adverse events related to the immune system occurring more than 3 months after transplantation included thrombocytopenia in one patient and hypothyroidism and alopecia in one other patient. Thymic transplantation is efficacious, well tolerated, and should be considered as treatment for infants with complete DiGeorge syndrome.

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38

Protheroe, A. "TCRBV family expansions persist following myeloablative chemotherapy and peripheral blood progenitor cell (PBPC) rescue." Immunology Letters 56, no. 1-3 (May 1997): 453. http://dx.doi.org/10.1016/s0165-2478(97)88683-x.

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39

Protheroe, A. S., P. W. M. Johnson, T. Craddock, C. Pickard, J. Henwood, J. Shefta, F. Lancaster, P. J. Selby, and A. W. Boylston. "TCRBV family expansions persist following myeloablative chemotherapy and peripheral blood progenitor cell (PBPC) rescue." Immunology Letters 56 (May 1997): 453. http://dx.doi.org/10.1016/s0165-2478(97)88854-2.

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40

Currier, J. R., K. S. Stevenson, and M. A. Robinson. "Molecular cloning and sequencing of cDNA encoding eight new rhesus macaque TCRBV gene families." Immunogenetics 51, no. 4-5 (April 4, 2000): 387–91. http://dx.doi.org/10.1007/s002510050635.

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41

Matsutani, Takaji, Takeshi Yoshioka, Yuji Tsuruta, Shoji Iwagami, Tomoko Toyosaki-Maeda, Takahiro Horiuchi, Akira B. Miura, et al. "Restricted usage of T-cell receptor α-chain variable region (TCRAV) and T-cell receptor β-chain variable region (TCRBV) repertoires after human allogeneic haematopoietic transplantation." British Journal of Haematology 109, no. 4 (June 2000): 759–69. http://dx.doi.org/10.1046/j.1365-2141.2000.02080.x.

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42

Breiteneder, Heimo, Otto Scheiner, Roswitha Hajek, Wolfgang Hulla, Robert H�ttinger, Gottfried Fischer, Dietrich Kraft, and Christof Ebner. "Diversity of TCRAV and TCRBV sequences used by human T-cell clones specific for a minimal epitope of Bet v 1, the major birch pollen allergen." Immunogenetics 42, no. 1 (May 1995): 53–58. http://dx.doi.org/10.1007/bf00164987.

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43

Maas, I. W. H. M., H. M. Schoemaker, R. H. W. M. Derksen, G. T. Spierenburg, and F. H. J. Gmelig-Meyling. "TCRBV-family expression among HPRT mutant T cell clones from patients with systemic lupus erythematosus." Immunology Letters 56 (May 1997): 363. http://dx.doi.org/10.1016/s0165-2478(97)86466-8.

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44

Maas, I. "TCRBV-family expression among HPRT mutant T cell clones from patients with systemic lupus erythematosus." Immunology Letters 56, no. 1-3 (May 1997): 363. http://dx.doi.org/10.1016/s0165-2478(97)88304-6.

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45

Deulofeut, Harold, Jeffrey L. Wilderson, Karyl S. Barron, and Mary Ann Robinson. "TCRBV 12 genes are polymorphic but the protein products encoded by each gene are conserved." Human Immunology 43, no. 3 (July 1995): 227–30. http://dx.doi.org/10.1016/0198-8859(94)00152-g.

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46

Balas, A., M. D. Garcia-Novo, J. Martinez, F. Garcı́a-Sánchez, S. Santos, and J. L. Vicario. "Intestinal αβ T cells of symptomatic celiac disease patients show oligoclonal TCRBV repertoire but polyclonal rearrangement patterns." Human Immunology 61, no. 3 (March 2000): 247–54. http://dx.doi.org/10.1016/s0198-8859(99)00152-4.

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47

Menssen, Antje, Sigrid Vollmer, Paul Trommler, Christian Sander, and Jörg C. Prinz. "Analysis of the TCRBV Repertoire of T Cells in Normal, Human Skin: Evidence for a Restricted Diversity." Journal of Investigative Dermatology 115, no. 1 (July 2000): 66–73. http://dx.doi.org/10.1046/j.1523-1747.2000.00982.x.

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48

Schito, Anna M., Eric Vittinghoff, Frederick M. Hecht, Mary K. Elkins, James O. Kahn, Jay A. Levy, and Jorge R. Oksenberg. "Longitudinal analysis of T-cell receptor gene use by CD8+ T cells in early human immunodeficiency virus infection in patients receiving highly active antiretroviral therapy." Blood 97, no. 1 (January 1, 2001): 214–20. http://dx.doi.org/10.1182/blood.v97.1.214.

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Abstract The effects of early antiretroviral therapy on the peripheral CD8+ T-cell population were assessed by sequentially determining the T-cell receptor (TCR) repertoire complexity in a cohort of 15 individuals recently diagnosed with human immunodeficiency virus infection. Analysis was based on quantitative TCR variable B gene (TCRBV) usage and complementary-determining region 3 length assessment. Repertories were assessed at baseline and at weeks 2, 4, 12, 24, and 72 after initiation of therapy. Early administration of highly active antiretroviral therapy has a positive effect on the preservation and homeostasis of the CD8+ cell repertoire. Nevertheless, differences from average baseline and control TCR profiles and initial development of repertoire perturbations were observed. The findings suggest that additional therapeutic protocols will be required during primary infection to significantly prevent long-term erosion of the T-cell–mediated immune response.

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49

Liao, L., A. Marinescu, A. Molano, C. Ciurli, R. P. Sekaly, J. D. Fraser, A. Popowicz, and D. N. Posnett. "TCR binding differs for a bacterial superantigen (SEE) and a viral superantigen (Mtv-9)." Journal of Experimental Medicine 184, no. 4 (October 1, 1996): 1471–82. http://dx.doi.org/10.1084/jem.184.4.1471.

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Both superantigens (SAG) and many anti-TCR monoclonal antibodies (mAb) have specificity for the V beta region of the TCR encoded by TCRBV genes. For instance the bacterial SAG staphylococcal enterotoxin E (SEE), the retroviral SAG MTV-9 and the mAb OT145 each react with human T cells expressing BV6S7. This BV gene encodes two common alleles. We found that SEE and the mAb preferentially activate T cells expressing BV6S7*1 as opposed to BV6S7*2, but Mtv-9 activates T cells expressing either allele. Thus binding to the TCR differs between the two SAGs. A mutation in the TCR HVR-4 region of BV6S7*1 (G72E), where the two BV6S7 alleles differ, indicated that HVR-4 is a component of the binding site for SEE and for the mAb OT145. BV6S7*2 has a charged E72 which may result in electrostatic repulsion of SEE, as SEE contains a similarly acidic aspartic acid residue at a TCR interaction site (204D).

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50

Foglietta, Myriam, Sara Mariani, Barbara Castella, Marta Coscia, Laura Godio, Serena Zappia, Mario Boccadoro, and Massimo Massaia. "Regulatory T Cells (Tregs) Are Highly Preserved in Multiple Myeloma Patients and Can Dominate Effector Functions." Blood 108, no. 11 (November 16, 2006): 658. http://dx.doi.org/10.1182/blood.v108.11.658.658.

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Abstract Naturally occurring CD4+CD25+ T regulatory cells (Tregs) are a subpopulation of CD4+ T cells playing a key role in lymphocyte homeostasis and maintenance of tolerance. Tregs play a key role in hampering anti-tumor immune surveillance by regulating immune responses against tumor cells. Depletion of Tregs yields to improved anti-tumor immune responses in both preclinical and clinical settings. Contradictory data have been reported in the frequency and function of Tregs cells in multiple myeloma (MM). The aim of this study was to characterize MM Tregs from the phenotypic, molecular and functional standpoints. We studied both peripheral blood (PB) and bone marrow (BM) samples from patients with symptomatic MM and from healthy donors. CD4+CD25high Tregs were normally represented in both PB and BM of MM patients and expressed a memory and activated phenotype. No differences were observed between PB and BM Tregs of healthy donors and MM patients, based on the expression of CD45R0, HLADR, CD40L and CD69 cell surface antigens. Flow cytometry was also used to assess the intracellular expression of Foxp3, a transcription factor which is crucial for the inhibitory function of Tregs cells. More than 90% of CD4+CD25high T cells were Foxp3+ in the PB and BM of MM patients and healthy donors. CD4+CD25+ T cells were purified from PB of newly diagnosed MM by MACS sorting. These cells were anergic to the stimulation via TCR and as effective as normal donor-derived CD4+CD25+ cells in inhibiting the TCR-mediated proliferation of autologous CD4+CD25- counterparts. To investigate whether clonal restriction had occurred in MM Tregs, we studied TCR diversity of CD4+CD25+ and CD4+CD25- cells by determining the reciprocal usage of BV gene segments (TCRBV repertoire) with a novel multiplex polymerase chain reaction assay recently developed in our laboratory. Our results demonstrate an highly preserved polyclonal TCRBV repertoire, providing the first evidence in cancer patients that TCR diversity of Tregs is not skewed by the long lasting exposure to tumor cells. Based on these data, we propose that inhibitory signals delivered by the highly preserved Tregs subset in MM can easily overwhelm the effector mechanisms of antitumor immunosurveillance which are deeply compromised in MM. Thus, depletion or neutralization of Tregs should be considered in future trials aimed at controlling the disease in MM patients by immune intervention.

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Journal articles on the topic 'TCRBV'

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