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T cells from Jak3-deficient mice have intact TCR signaling, but increased apoptosis
1Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
The Jak family tyrosine kinase, Jak3, is involved in signaling through cytokine receptors utilizing the common gamma-chain (gamma(c)). Mice and humans lacking Jak3 have severe immune deficiencies, including defects in B and T lymphocyte development and function. In particular, Jak3-deficient mice have mature T cells with an activated phenotype, yet these cells are functionally nonresponsive. In this work, we show that Jak3-deficient T cells have no gross defects in early T cell signaling, as measured by TCR-induced tyrosine phosphorylation and calcium mobilization responses. Furthermore, we find that Jak3-deficient mice expressing a transgenic TCR have extremely low numbers of peripheral T cells with a naive phenotype, indicating that both peripheral activation and expansion of Jak3-/- T cells are driven by antigenic signals. We show that, similar to gamma(c)-deficient mice, T cells from Jak3-deficient mice have an increased susceptibility to apoptosis. Previously, we showed that when stimulated in vitro by CD3 plus CD28 cross-linking, Jak3-/- T cells secrete greatly reduced amounts of IL-2, and fail to proliferate. However, by measuring intracellular IL-2 levels, we find that Jak3-/- T cells produce amounts of IL-2 similar to activated T cells from control mice, further supporting the notion that there is no defect in TCR signaling in Jak3-/- T cells.
The Jak family tyrosine kinase, Jak3, is involved in signaling through cytokine receptors utilizing the common gamma-chain (gamma(c)). Mice and humans lacking Jak3 have severe immune deficiencies, including defects in B and T lymphocyte development and function. In particular, Jak3-deficient mice have mature T cells with an activated phenotype, yet these cells are functionally nonresponsive. In this work, we show that Jak3-deficient T cells have no gross defects in early T cell signaling, as measured by TCR-induced tyrosine phosphorylation and calcium mobilization responses. Furthermore, we find that Jak3-deficient mice expressing a transgenic TCR have extremely low numbers of peripheral T cells with a naive phenotype, indicating that both peripheral activation and expansion of Jak3-/- T cells are driven by antigenic signals. We show that, similar to gamma(c)-deficient mice, T cells from Jak3-deficient mice have an increased susceptibility to apoptosis. Previously, we showed that when stimulated in vitro by CD3 plus CD28 cross-linking, Jak3-/- T cells secrete greatly reduced amounts of IL-2, and fail to proliferate. However, by measuring intracellular IL-2 levels, we find that Jak3-/- T cells produce amounts of IL-2 similar to activated T cells from control mice, further supporting the notion that there is no defect in TCR signaling in Jak3-/- T cells.