[HTML][HTML] Quantifying size and diversity of the human T cell alloresponse

S DeWolf, B Grinshpun, T Savage, SP Lau… - JCI insight, 2018 - ncbi.nlm.nih.gov
S DeWolf, B Grinshpun, T Savage, SP Lau, A Obradovic, B Shonts, S Yang, H Morris…
JCI insight, 2018ncbi.nlm.nih.gov
Alloreactive T lymphocytes are the primary mediators of immune responses in
transplantation, both in the graft-versus-host and host-versus-graft directions. While
essentially all clones comprising the human T cell repertoire have been selected on self-
peptide presented by self–human leukocyte antigens (self-HLAs), much remains to be
understood about the nature of clones capable of responding to allo-HLA molecules.
Quantitative tools to study these cells are critical to understand fundamental features of this …
Abstract
Alloreactive T lymphocytes are the primary mediators of immune responses in transplantation, both in the graft-versus-host and host-versus-graft directions. While essentially all clones comprising the human T cell repertoire have been selected on self-peptide presented by self–human leukocyte antigens (self-HLAs), much remains to be understood about the nature of clones capable of responding to allo-HLA molecules. Quantitative tools to study these cells are critical to understand fundamental features of this important response; however, the large size and diversity of the alloreactive T cell repertoire in humans presents a great technical challenge. We have developed a high-throughput T cell receptor (TCR) sequencing approach to characterize the human alloresponse. We present a statistical method to model T cell clonal frequency distribution and quantify repertoire diversity. Using these approaches, we measured the diversity and frequency of distinct alloreactive CD4+ and CD8+ T cell populations in HLA-mismatched responder-stimulator pairs. Our findings indicate that the alloimmune repertoire is highly specific for a given pair of individuals, that most alloreactive clones circulate at low frequencies, and that a high proportion of TCRs is likely able to recognize alloantigens.
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