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Tetramers Reveal CD4+ T Cells that are Specific for U1-70 in Systemic Lupus Erythematosus

Nicole Hanick Kattah

出版	Stanford University, 2010
ISBN	STANFORD:tg095rp3009
URL	http://books.google.com.hk/books?id=0YL2SSwM6Z0C&hl=&source=gbs_api
EBook	SAMPLE

註釋

Antigen-specific CD4+ T cells have been implicated in the autoimmune disease systemic lupus erythematosus (SLE), yet little is known about the function of these T cells or the precise peptide antigens that they recognize. We hypothesized that antigen-specific CD4+ T cells contribute to lupus pathology through two mechanisms: (1) by providing help to B cells for pathogenic autoantibody production, and (2) by directly promoting inflammation through the secretion of proinflammatory cytokines. We tested these two hypotheses by generating a series of MHC class II tetramers of I-Ek containing peptides from the spliceosomal protein U1-70. These tetramers specifically stained distinct CD4+ T cell populations in MRL/lpr mice. Using these reagents, we demonstrated that CD4+ T cells specific for U1-70 (131-150):I-Ek correlated with disease and with anti-U1-70 autoantibody production, expressed ROR[lowercase gamma]t and Tbet, and produced IFN[lowercase gamma] and IL-17A in an I-Ek-dependent manner. We confirmed our findings from mice in human patients with SLE and mixed connective tissue disease (MCTD). U1-70 specific CD4+ T cells obtained from peripheral blood mononuclear cells (PBMCs) of patients with SLE produced IFN[lowercase gamma] in all 5 patients tested and IL-17A in 1 out of 2 patients whose serum contained RNP autoantibodies. These data support the hypotheses that antigen-specific T cells recognize the same autoantigens as B cells, and that they produce proinflammatory cytokines. These studies represent the first reported tetramers for studying antigen-specific T cells in a mouse model of lupus, and demonstrate an antigen-specific source of IL-17A in human autoimmune disease.