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

2016; Nature Portfolio; Volume: 17; Issue: 6 Linguagem: Inglês

10.1038/ni.3424

1529-2916

Miguel Muñoz‐Ruiz, Julie C. Ribot, Ana Rita Grosso, Natacha Gonçalves‐Sousa, Ana Pamplona, Daniel J. Pennington, José R. Regueiro, Edgar Fernández-Malavé, Bruno Silva‐Santos,

Immunotherapy and Immune Responses

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.