International Immunology, Vol. 15, No. 11, pp. 1359-1367,
November 2003
© 2003 Japanese Society for Immunology
TCR-mediated hyper-responsiveness of autoimmune G
i2-/- mice is an intrinsic naïve CD4+ T cell disorder selective for the Gi2 subunit
1 Pathology and Laboratory Medicine, 2 Digestive Diseases, 3 Microbiology, Immunology and Molecular Genetics, 4 Molecular, Cellular and Developmental Biology, 5 Molecular Biology Institute, University of California at Los Angeles, Los Angeles, CA 90095, USA 6 VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA 7 Present address: Laboratory of Signal Transduction, and Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA 8 Present address: Bristol-Myers Squibb Co., Princeton, NJ, USA
Correspondence to: J. Braun, Pathology and Medicine, UCLA, Box 951732, CHS 13-222, Los Angeles, CA 90095-1732, USA. E-mail: jbraun{at}mednet.ucla.edu
Transmitting editor: C. Terhorst
Heterotrimeric Gi signaling regulates immune homeostasis, since autoimmunity occurs upon disruption of this pathway. However, the role of the lymphocyte-expressed G
i subunits (Gi2 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 Gi2 or Gi3 subunits. Gi2-/- but not Gi3-/- splenocytes were hyper-responsive for IFN-
and IL-4 production following activation through the TCR. Gi2-/- T cells had a relaxed costimulatory requirement for IL-2 secretion and proliferation compared to wild-type cells. Purified naïve Gi2-/- 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 Gi2-/- memory T cells, but involved an intrinsic T cell alteration. Cytokine hyper-responsiveness was not seen when purified Gi2-/- T cells were stimulated with phorbol myristic acetate/ionomycin, localizing the alteration to a proximal TCR-specific signaling pathway. Gi2-/- CD4+ T cells were distinguished from wild-type or Gi3-/- T cells by a globally augmented TCR-induced calcium response. These findings indicate that Gi2-/- mice have an intrinsic CD4+ T cell abnormality in TCR signaling which may be one cause of augmented T cell effector function and Gi2-/- autoimmune susceptibility.
Keywords: autoimmunity, mucosa, signal transduction, T lymphocytes, TCR
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