vivit-peptide and Leishmaniasis--Cutaneous

Transcription factors of the nuclear factor of activated T cells (NFAT) family are thought to regulate the expression of a variety of inducible genes such as interleukin-2 (IL-2), IL-4, and tumor necrosis factor-alpha. However, it remains unresolved whether NFAT proteins play a role in regulating transcription of the interferon- gamma (IFN-gamma) gene. Here it is shown that the transcription factor NFAT1 (NFATc2) is a major regulator of IFN-gamma production in vivo. Compared with T cells expressing NFAT1, T cells lacking NFAT1 display a substantial IL-4-independent defect in expression of IFN-gamma mRNA and protein. Reduced IFN-gamma production by NFAT1(-/-)x IL-4(-/-) T cells is observed after primary in vitro stimulation of naive CD4+ T cells, is conserved through at least 2 rounds of T-helper cell differentiation, and occurs by a cell-intrinsic mechanism that does not depend on overexpression of the Th2-specific factors GATA-3 and c-Maf. Concomitantly, NFAT1(-/-)x IL-4(-/-) mice show increased susceptibility to infection with the intracellular parasite Leishmania major. Moreover, IFN-gamma production in a murine T-cell clone is sensitive to the selective peptide inhibitor of NFAT, VIVIT. These results suggest that IFN-gamma production by T cells is regulated by NFAT1, most likely at the level of gene transcription.

Topics: Animals; CD4-Positive T-Lymphocytes; Cell Differentiation; Cell Line; Culture Media, Serum-Free; DNA-Binding Proteins; Gene Expression Regulation; Immunity, Innate; Interferon-gamma; Interleukin-4; Leishmania major; Leishmaniasis, Cutaneous; Lymphocyte Activation; Mice; Mice, Knockout; NFATC Transcription Factors; Nuclear Proteins; Oligopeptides; Recombinant Fusion Proteins; RNA, Messenger; T-Lymphocyte Subsets; Th1 Cells; Th2 Cells; Transcription Factors; Transcription, Genetic; Transfection