TCR signal strength controls thymic differentiation of discrete proinflammatory γδ T cell subsets

The mouse thymus produces discrete gamma delta T cell subsets that make either interferon-gamma (IFN-gamma) or interleukin 17 (IL-17), but the role of the T cell antigen receptor (TCR) in this developmental process remains controversial. Here we show that Cd3g(+/-) Cd3d(+/-) (CD3 double-haploinsufficient (CD3DH)) mice have reduced TCR expression and signaling strength on gamma delta T cells. CD3DH mice had normal numbers and phenotypes of alpha beta thymocyte subsets, but impaired differentiation of fetal V gamma 6(+) (but not V gamma 4(+)) IL-17-producing gamma delta T cells and a marked depletion of IFN-gamma-producing CD122(+) NK1.1(+) gamma delta T cells throughout ontogeny. Adult CD3DH mice showed reduced peripheral IFN-gamma(+) gamma delta T cells and were resistant to experimental cerebral malaria. Thus, TCR signal strength within specific thymic developmental windows is a major determinant of the generation of proinflammatory gamma delta T cell subsets and their impact on pathophysiology.