Human TCR-MHC coevolution after divergence from mice includes increased nontemplate-encoded CDR3 diversity

X Chen, L Poncette, T Blankenstein - Journal of Experimental Medicine, 2017 - rupress.org
X Chen, L Poncette, T Blankenstein
Journal of Experimental Medicine, 2017rupress.org
For thymic selection and responses to pathogens, T cells interact through their αβ T cell
receptor (TCR) with peptide–major histocompatibility complex (MHC) molecules on antigen-
presenting cells. How the diverse TCRs interact with a multitude of MHC molecules is
unresolved. It is also unclear how humans generate larger TCR repertoires than mice do.
We compared the TCR repertoire of CD4 T cells selected from a single mouse or human
MHC class II (MHC II) in mice containing the human TCR gene loci. Human MHC II yielded …
For thymic selection and responses to pathogens, T cells interact through their αβ T cell receptor (TCR) with peptide–major histocompatibility complex (MHC) molecules on antigen-presenting cells. How the diverse TCRs interact with a multitude of MHC molecules is unresolved. It is also unclear how humans generate larger TCR repertoires than mice do. We compared the TCR repertoire of CD4 T cells selected from a single mouse or human MHC class II (MHC II) in mice containing the human TCR gene loci. Human MHC II yielded greater thymic output and a more diverse TCR repertoire. The complementarity determining region 3 (CDR3) length adjusted for different inherent V-segment affinities to MHC II. Humans evolved with greater nontemplate-encoded CDR3 diversity than did mice. Our data, which demonstrate human TCR–MHC coevolution after divergence from rodents, explain the greater T cell diversity in humans and suggest a mechanism for ensuring that any V–J gene combination can be selected by a single MHC II.
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