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

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.