Normal pathogen-specific immune responses mounted by CTLA-4-deficient T cells: a paradigm reconsidered

CTLA-4 is a critical negative regulator of T cell responses and CTLA-4-defi cient (CTLA-4(-/-)) mice die of a lymphproliferative disease. Nevertheless, RAG-2-deficient mice reconstituted with a mixture of CTLA-4(-/-) and norma l (CTLA-4(+/+)) bone marrow survive in the absence of any signs of disease, although 50% of their T cells do not express CTLA-4. Using such mixed chim eras, we analyzed the role of CTLA-4 in specific T cell responses to lympho cytic choriomeningitis virus, Leishmania major and mouse mammary tumor viru s, which cause acute, chronic and persistent infections, respectively. The populations of antigen-specific CTLA-4(-/-)CD4(+) and CTLA-4(-/-)CD8(+) T c ells became activated, expanded and contracted indistinguishably from CTLA- 4(+/+)CD4(+) and CTLA-4(+/+)CD8(+) T cells after infection with all three p athogens. Thus, CTLA-4 is not involved in the down-regulation of specific T cell responses and peripheral deletion in a T cell-autonomous fashion.