The characterization of the human T-cell receptor （TCR） repertoire has made remarkable progress, with most of the work focusing on the TCRβ chains. Here, we ana- lyzed the diversity and complexity of both the TCRa ...The characterization of the human T-cell receptor （TCR） repertoire has made remarkable progress, with most of the work focusing on the TCRβ chains. Here, we ana- lyzed the diversity and complexity of both the TCRa and TCRβ repertoires of three healthy donors. We found that the diversity of the TCRα repertoire is higher than that of the TCRβ repertoire, whereas the usages of the V and J genes tended to be preferential with similar TRAV and TRAJ patterns in all three donors. The V-J pairings, like the V and J gene usages, were slightly preferential. We also found that the TRDV1 gene rearranges with the majority of TRAJ genes, suggesting that TRDV1 is a shared TRAV/DV gene （TRAV42/DV1）. Moreover, we uncovered the presence of tandem TRBD （TRB D gene） usage in -2% of the productive human TCRβ CDR3 sequences.展开更多
T cells and T cell receptors(TCRs)play pivotal roles in adaptive immune responses against tumors.The development of next-generation sequencing technologies has enabled the analysis of the TCRb repertoire usage.Given t...T cells and T cell receptors(TCRs)play pivotal roles in adaptive immune responses against tumors.The development of next-generation sequencing technologies has enabled the analysis of the TCRb repertoire usage.Given the scarce investigations on the TCR repertoire in lung cancer tissues,in this study,we analyzed TCRb repertoires in lung cancer tissues and the matched distant non-tumor lung tissues(normal lung tissues)from 15 lung cancer patients.Based on our results,the general distribution of T cell clones was similar between cancer tissues and normal lung tissues;however,the proportion of highly expanded clones was significantly higher in normal lung tissues than in cancer tissues(0.021%±0.002%vs.0.016%±0.001%,P=0.0054,Wilcoxon signed rank test).In addition,a significantly higher TCR diversity was observed in cancer tissues than in normal lung tissues(431.37±305.96 vs.166.20±101.58,P=0.0075,Mann-Whitney U test).Moreover,younger patients had a significantly higher TCR diversity than older patients(640.7±295.3 vs.291.8±233.6,P=0.036,Mann-Whitney U test),and the higher TCR diversity in tumors was significantly associated with worse cancer outcomes.Thus,we provided a comprehensive comparison of the TCR repertoires between cancer tissues and matched normal lung tissues and demonstrated the presence of distinct T cell immune microenvironments in lung cancer patients.展开更多
Background We distinguished graft-versus-host disease (GVHD) from graft-versus-leukemia (GVL) effects and to investigate the distribution of T-cell receptor (TCR) Vβ gene repertoire in individuals with leukemia befor...Background We distinguished graft-versus-host disease (GVHD) from graft-versus-leukemia (GVL) effects and to investigate the distribution of T-cell receptor (TCR) Vβ gene repertoire in individuals with leukemia before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods Peripheral blood mononuclear cells (PBMC) were obtained from 10 normal individuals, 8 donors and 11 patients with leukemia before and after transplantation. Polymerase chain reaction (PCR) amplification of complementarity-determining region 3 (CDR3) of 24 TCR Vβ genes was used to examine serial samples of PBMC. The PCR products were further analyzed by genescan to evaluate clonality of T cells.Results The 24 TCR Vβ gene repertoire displayed highly diverse and polyclonal spectratypes in all normal individuals and 4 of 8 donors. Anoth er 4 donors expressed part of the 24 TCR Vβ subfamily and 1 donor had oligoclonality. The expressions of the 24 TCR Vβ subfamilies were skewed and restric ted in 11 leukemia patients before and after transplantation. Some absences of 24 TCR Vβ subfamily expression were quite similar between the recipients pro-transplantation and related donors. The number of subfamilies expressed increased over time post-transplantation, but the restricted expressions of the subfamily could last 6-30 months after transplantation. All patients with GVHD and some without GVHD exhibited T cell clonal expansion. The expansive T cell clone was distributed in Vβ 2-3, 16-17, 18-19, 21 and Vβ 23 in patients with GVHD and in Vβ 7, 9, 16 and 19 in patients without GVHD. One patient with syngeneic-HSCT (syn-HSCT) had Vβ 15 and 16 T cell expansion after transplantation. One patient displayed Vβ 18 T cell expansion after donor lymphocyte infusion (DLI).Conclusions Normal individuals express the entire 24 TCR Vβ ge ne repertoire and have polyclonal distribution. However, the TCR Vβ gene repertoire is only partially expressed in some donors. The TCR Vβ gene repertoire is restrictedly expressed in a skew fashion in patients with leukemia before and after transplantation. The number of TCR Vβ gene subfamilies increases over time post- transplantation. GVHD and GVL effects may induce the proliferation of T cell clones.Clinical GVL response may be distinguished from GVHD alloreactivity through the host MHC antigen.展开更多
基金We thank Dr. Christopher J. Vavrickafor and Boris Tefsen for their critical reading and revision of the manuscript and Dr. Miles P. Dav- enport for his inspiring discussions. This work is supported by the National Natural Science Foundation of China （NSFC, Grant No. 31030030）, the National Basic Research Program （973 Program） （No. 2013CB531500） and the National Natural Science Foundation of China （Grant No. 81373141 ）. G.F.G. is a leading principal investigator of the NSFC Innovative Research Group （Grant No. 81321063）.
文摘The characterization of the human T-cell receptor （TCR） repertoire has made remarkable progress, with most of the work focusing on the TCRβ chains. Here, we ana- lyzed the diversity and complexity of both the TCRa and TCRβ repertoires of three healthy donors. We found that the diversity of the TCRα repertoire is higher than that of the TCRβ repertoire, whereas the usages of the V and J genes tended to be preferential with similar TRAV and TRAJ patterns in all three donors. The V-J pairings, like the V and J gene usages, were slightly preferential. We also found that the TRDV1 gene rearranges with the majority of TRAJ genes, suggesting that TRDV1 is a shared TRAV/DV gene （TRAV42/DV1）. Moreover, we uncovered the presence of tandem TRBD （TRB D gene） usage in -2% of the productive human TCRβ CDR3 sequences.
基金supported by the CAMS Innovation Fund for Medical Sciences(CIFMS),China(Grant No.2016-I2M-1-001)the National Key Research and Development Program of China(Grant No.2017YFC0908401)the National Basic Research Program of China(973 Program,Grant No.2014CBA02004)
文摘T cells and T cell receptors(TCRs)play pivotal roles in adaptive immune responses against tumors.The development of next-generation sequencing technologies has enabled the analysis of the TCRb repertoire usage.Given the scarce investigations on the TCR repertoire in lung cancer tissues,in this study,we analyzed TCRb repertoires in lung cancer tissues and the matched distant non-tumor lung tissues(normal lung tissues)from 15 lung cancer patients.Based on our results,the general distribution of T cell clones was similar between cancer tissues and normal lung tissues;however,the proportion of highly expanded clones was significantly higher in normal lung tissues than in cancer tissues(0.021%±0.002%vs.0.016%±0.001%,P=0.0054,Wilcoxon signed rank test).In addition,a significantly higher TCR diversity was observed in cancer tissues than in normal lung tissues(431.37±305.96 vs.166.20±101.58,P=0.0075,Mann-Whitney U test).Moreover,younger patients had a significantly higher TCR diversity than older patients(640.7±295.3 vs.291.8±233.6,P=0.036,Mann-Whitney U test),and the higher TCR diversity in tumors was significantly associated with worse cancer outcomes.Thus,we provided a comprehensive comparison of the TCR repertoires between cancer tissues and matched normal lung tissues and demonstrated the presence of distinct T cell immune microenvironments in lung cancer patients.
基金ThisstudywassupportedbytheNationalNatureScienceFoundationofChina (NO 3 9970 70 6)
文摘Background We distinguished graft-versus-host disease (GVHD) from graft-versus-leukemia (GVL) effects and to investigate the distribution of T-cell receptor (TCR) Vβ gene repertoire in individuals with leukemia before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods Peripheral blood mononuclear cells (PBMC) were obtained from 10 normal individuals, 8 donors and 11 patients with leukemia before and after transplantation. Polymerase chain reaction (PCR) amplification of complementarity-determining region 3 (CDR3) of 24 TCR Vβ genes was used to examine serial samples of PBMC. The PCR products were further analyzed by genescan to evaluate clonality of T cells.Results The 24 TCR Vβ gene repertoire displayed highly diverse and polyclonal spectratypes in all normal individuals and 4 of 8 donors. Anoth er 4 donors expressed part of the 24 TCR Vβ subfamily and 1 donor had oligoclonality. The expressions of the 24 TCR Vβ subfamilies were skewed and restric ted in 11 leukemia patients before and after transplantation. Some absences of 24 TCR Vβ subfamily expression were quite similar between the recipients pro-transplantation and related donors. The number of subfamilies expressed increased over time post-transplantation, but the restricted expressions of the subfamily could last 6-30 months after transplantation. All patients with GVHD and some without GVHD exhibited T cell clonal expansion. The expansive T cell clone was distributed in Vβ 2-3, 16-17, 18-19, 21 and Vβ 23 in patients with GVHD and in Vβ 7, 9, 16 and 19 in patients without GVHD. One patient with syngeneic-HSCT (syn-HSCT) had Vβ 15 and 16 T cell expansion after transplantation. One patient displayed Vβ 18 T cell expansion after donor lymphocyte infusion (DLI).Conclusions Normal individuals express the entire 24 TCR Vβ ge ne repertoire and have polyclonal distribution. However, the TCR Vβ gene repertoire is only partially expressed in some donors. The TCR Vβ gene repertoire is restrictedly expressed in a skew fashion in patients with leukemia before and after transplantation. The number of TCR Vβ gene subfamilies increases over time post- transplantation. GVHD and GVL effects may induce the proliferation of T cell clones.Clinical GVL response may be distinguished from GVHD alloreactivity through the host MHC antigen.
