Abstract
Recent advances in high throughput sequencing (HTS) of T cell receptors (TCRs) and in transcriptomic analysis, particularly at the single cell level, have opened the door to a new level of understanding of human immunology and immune-related diseases. In this article, we discuss the use of HTS of TCRs to discern the factors controlling human T cell repertoire development and how this approach can be used in combination with human immune system (HIS) mouse models to understand human repertoire selection in an unprecedented manner. An exceptionally high proportion of human T cells has alloreactive potential, which can best be understood as a consequence of the processes governing thymic selection. High throughput TCR sequencing has allowed assessment of the development, magnitude and nature of the human alloresponse at a new level and has provided a tool for tracking the fate of pre-transplant-defined donor- and host-reactive TCRs following transplantation. New insights into human allograft rejection and tolerance obtained with this method in combination with single cell transcriptional analyses are reviewed here.
Highlights
The extraordinary magnitude of the T cell alloresponse is the most significant barrier to successful organ and hematopoietic cell transplantation
The ease with which strong alloresponses can be elicited by naïve T cell populations in vitro in mixed lymphocyte reactions (MLRs) and cellmediated lympholysis (CML) assays reflects the unusual strength of this response, in contrast to responses against pathogens, which typically require priming in order to elicit measurable in vitro responses
Despite the very divergent CDR3b T cell receptors (TCRs) repertoires, we found that V and J gene usage in different cell populations in human thymi was overall very similar among different mice generated with different hematopoietic stem cells (HSCs) and different thymi
Summary
The extraordinary magnitude of the T cell alloresponse is the most significant barrier to successful organ and hematopoietic cell transplantation. Chronic rejection and GVHD persist as common complications of organ and hematopoietic cell transplantation, respectively, despite these advances All of these difficulties reflect, in large part, the unusual features of alloresponses compared to typical immune responses to pathogens. Human leukocyte antigens (HLA), the MHC antigens specific to humans, arise from more than 220 genes located on the short arm of human chromosome 6, and include more than 25,000 alleles [1] This polymorphism is believed to have evolved to allow sufficient diversity within the species so that T cells of at least some individuals can respond to new infections without the entire species being eradicated by new organisms that might succeed in evading a less varied immune response. It is likely that myriads of allogeneic HLA/peptide molecule specificities are recognized as alloantigens This assumption is consistent with the very high proportion and number of unique alloreactive TCR sequences that have been detected in TCR sequencing studies [5]. We summarize studies using this methodology to understand the development of human TCR repertoires in human immune system (HIS) mouse models and how this understanding bears on autoreactivity and alloreactivity
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