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

The murine thymus produces discrete γδ T cell subsets making either interferon-γ (IFN--γ) or interleukin 17 (IL-17), but the role of the TCR in this developmental process remains controversial. Here we show that mice haploinsufficient for both Cd3g and Cd3d (CD3DH, for CD3 double haploinsufficient) have reduced TCR expression and signaling strength selectively on γδ T cells. CD3DH mice had normal numbers and phenotype 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.