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

The thymus produces γδ T cell subsets making either IFN-γ or IL-17. Silva-Santos and colleagues show that TCR signal strength within specific developmental windows is a major determinant of the generation of these γδ T cell subsets. The mouse thymus produces discrete γδ T cell subsets that make either interferon-γ (IFN-γ) 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 γδ T cells. CD3DH mice had normal numbers and phenotypes of αβ thymocyte subsets, but impaired differentiation of fetal Vγ6 + (but not Vγ4 + ) IL-17-producing γδ T cells and a marked depletion of IFN-γ-producing CD122 + NK1.1 + γδ T cells throughout ontogeny. Adult CD3DH mice showed reduced peripheral IFN-γ + γδ 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 γδ T cell subsets and their impact on pathophysiology.