Different composition of the human and the mouse γδT cell receptor explains different phenotypes of CD3γ and CD3δ immunodeficiencies

The gamma delta T cell receptor for antigen (TCR) comprises the clonotypic TCR gamma delta, the CD3 (CD3 gamma epsilon and/or CD3 delta epsilon), and the xi xi dimers. gamma delta T cells do not develop in CD3 gamma-deficient mice, whereas human patients lacking CD3 gamma have abundant peripheral blood gamma delta T cells expressing high gamma delta TCR levels. In an attempt to identify the molecular basis for these discordant phenotypes, we determined the stoichiometries of mouse and human gamma delta TCRs using blue native polyacrylamide gel electrophoresis and anti-TCR-specific antibodies. The gamma delta TCR isolated in digitonin from primary and cultured human gamma delta T cells includes CD3 gamma, with a TCR gamma delta CD3 epsilon(2)delta gamma xi(2) stoichiometry. In CD3 gamma-deficient patients, this may allow substitution of CD3 gamma by the CD3 delta chain and thereby support gamma delta T cell development. In contrast, the mouse gamma delta TCR does not incorporate CD3 delta and has a TCR gamma CD3 epsilon(2)gamma(2)xi(2) stoichiometry. CD3 gamma-deficient mice exhibit a block in gamma delta T cell development. A human, but not a mouse, CD3 delta transgene rescues gamma delta T cell development in mice lacking both mouse CD3 delta and CD3 gamma chains. This suggests important structural and/or functional differences between human and mouse CD3 delta chains during gamma delta T cell development. Collectively, our results indicate that the different gamma delta T cell phenotypes between CD3 gamma-deficient humans and mice can be explained by differences in their gamma delta TCR composition.