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TCRγ constant usage tunes human γδ T cell antigen sensitivity, thymic programming, and peripheral function.

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Human gamma delta T cell receptors (TCRs) show that constant domains, not just antigen recognition, control activation. Cγ1 and Cγ2 constant domains influence T cell function and expansion, impacting immune responses.

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Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • T cell activation is typically linked to antigen recognition strength via variable complementarity-determining region loops.
  • The role of constant domains in T cell receptor (TCR) function, particularly in gamma delta (γδ) T cells, remains less understood.

Purpose of the Study:

  • To investigate the role of human γδ TCR constant domains (Cγ) in modulating T cell activation and phenotype.
  • To determine if Cγ usage influences T cell differentiation, effector functions, and in vivo clonal expansion.

Main Methods:

  • Single-cell RNA sequencing was employed to analyze Cγ usage in human T cells.
  • Phenotypic analysis and assessment of effector molecule expression (e.g., granzyme) were performed.
  • Selective expansion of TCRs in colorectal tumors was investigated.

Main Results:

  • Cγ constant domain usage correlates with distinct T cell phenotypes, independent of variable region antigen recognition.
  • Cγ1 usage is associated with a differentiated cytotoxic effector phenotype, higher granzyme expression, and selective expansion in colorectal tumors.
  • Cγ2 usage is linked to naïve phenotypes during development and functions in inhibition and wound healing in peripheral tissues.

Conclusions:

  • Human γδ TCR constant domains (Cγ1 and Cγ2) act as modulators of T cell activation intensity.
  • Cγ usage significantly impacts γδ T cell phenotype, differentiation, and clonal expansion throughout their lifespan.
  • This provides an additional regulatory mechanism for human γδ T cell function beyond antigen specificity.