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Cytotoxic T lymphocyte antigen-4 (CTLA-4) is constitutively expressed on CD25+CD4+ regulatory T cells (Treg) and is suggested to play a role in Treg-mediated suppression. However, the results of analysis with anti-CTLA-4 have been controversial. We addressed this issue by analyzing mice over-expressing or deficient in CTLA-4. For over-expression, CTLA-4 transgenic mice expressing a full-length (FL) or a truncated (TL) mutant of CTLA-4 were analyzed. FL T cells expressed similar levels of CTLA-4 to Treg, whereas TL T cells expressed much higher levels on the cell surface. The number of Treg in both mice was decreased, although Foxp3 expression was not altered. Treg from both mice exerted suppressive activity, whereas CD25- T cells from FL mice showed no suppression. Furthermore, CD25+CD4 thymocytes from young CTLA-4-deficient mice were analyzed and found to exhibit suppressive activity. These results indicate that Treg exert in vitro suppressive activity independent of CTLA-4 expression. [ABSTRACT FROM AUTHOR]

Gads is a Grb2-like adaptor protein expressed in hematopoietic cells. We demonstrated that mast cells from Gads−/− mice have selective functional defects. Bone marrow-derived mast cells from Gads−/− mice failed to induce Ca2+ mobilization, degranulation and cytokine production upon cross-linking of FcεRI. In vivo passive cutaneous anaphylaxis was also greatly impaired in Gads−/− mice. In contrast, Gads was dispensable for Toll-like receptor-mediated cytokine production in mast cells. Accordingly, mast cell-dependent resistance to acute peritoneal bacterial infection is not reduced in Gads−/− mice in vivo. Moreover, mature T and B cell responses and antibody production upon immunization were apparently normal in Gads−/− mice. Thus, inhibition of Gads in vivo would suppress the IgE-mediated allergic reaction with minimum adverse effects on both innate and acquired immune responses, and Gads could be an ideal target for the control of allergic responses. [ABSTRACT FROM AUTHOR]