TCR-mediated hyper-responsiveness of autoimmune Gαi2-/- mice is an intrinsic naïve CD4+ T cell disorder selective for the Gαi2 subunit

Abstract

Heterotrimeric Gi signaling regulates immune homeostasis, since autoimmunity occurs upon disruption of this pathway. However, the role of the lymphocyte-expressed Gαi subunits (Gαi2 and 3) on T cell activation and cytokine production is poorly understood. To examine this role, we studied T lymphocytes from mice deficient in the Gαi2 or Gαi3 subunits. Gαi2-/- but not Gαi3-/- splenocytes were hyper-responsive for IFN-γ and IL-4 production following activation through the TCR. Gαi2-/- T cells had a relaxed costimulatory requirement for IL-2 secretion and proliferation compared to wild-type cells. Purified naïve Gαi2-/- T cells produced more IL-2 than naïve wild-type T cells following TCR activation, indicating that the hyper-responsive cytokine profile was not due to the expanded Gαi2-/- memory T cells, but involved an intrinsic T cell alteration. Cytokine hyperresponsiveness was not seen when purified Gαi2-/- T cells were stimulated with phorbol myristic acetate/ionomycin, localizing the alteration to a proximal TCR-specific signaling pathway. Gαi2-/- CD4+ T cells were distinguished from wild-type or Gαi3-/- T cells by a globally augmented TCR-induced calcium response. These findings indicate that Gαi2-/- mice have an intrinsic CD4+ T cell abnormality in TCR signaling which may be one cause of augmented T cell effector function and Gαi2-/- autoimmune susceptibility.