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

Nat Immunol. 2016 Jun;17(6):721-727. doi: 10.1038/ni.3424. Epub 2016 Apr 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / metabolism
  • Cell Differentiation*
  • Cells, Cultured
  • Disease Models, Animal
  • Humans
  • Inflammation / immunology*
  • Interferon-gamma / metabolism
  • Interleukin-17 / metabolism
  • Interleukin-2 Receptor beta Subunit / metabolism
  • Malaria, Cerebral / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NK Cell Lectin-Like Receptor Subfamily B / metabolism
  • Receptors, Antigen, T-Cell, gamma-delta / genetics
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • Signal Transduction
  • T-Lymphocyte Subsets / physiology*
  • T-Lymphocytes / physiology*
  • Thymus Gland / immunology*


  • Antigens, Ly
  • Il2rb protein, mouse
  • Interleukin-17
  • Interleukin-2 Receptor beta Subunit
  • Klrb1c protein, mouse
  • NK Cell Lectin-Like Receptor Subfamily B
  • Receptors, Antigen, T-Cell, gamma-delta
  • T-cell receptor Vgamma6, mouse
  • Interferon-gamma