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Cytotoxic T-lymphocyte antigen 4 ( CTLA-4) -mediated regulation of already tolerized autoreactive T cells is critical for understanding autoimmune responses. Although defects in CTLA-4 contribute to abnormal FOXP3+ regulatory T (Treg) cell function in rheumatoid arthritis, its role in autoreactive T cells remains elusive. We studied immunity towards the dominant collagen type II ( CII) T-cell epitope in collagen-induced arthritis both in the heterologous setting and in the autologous setting where CII is mutated at position E266D in mouse cartilage. CTLA-4 regulated all stages of arthritis, including the chronic phase, and affected the priming of autologous but not heterologous CII-reactive T cells. CTLA-4 expression by both conventional T (Tconv) cells and Treg cells was required but while Tconv cell expression was needed to control the priming of naive autoreactive T cells, CTLA-4 on Treg cells prevented the inflammatory tissue attack. This identifies a cell-type-specific time window when CTLA-4-mediated tolerance is most powerful, which has important implications for clinical therapy with immune modulatory drugs. [ABSTRACT FROM AUTHOR]

Antigen presentation by the MHC- II to CD4+ T cells is important in adaptive immune responses. The class II transactivator ( CIITA in human and C2 TA in mouse) is the master regulator of MHC- II gene expression. It coordinates the transcription factors necessary for the transcription of MHC- II molecules. In humans, genetic variations in CIITA have been associated with differential expression of MHC- II and susceptibility to autoimmune diseases. Here we made use of a C2ta congenic mouse strain (expressing MHC- II haplotype H-2q) to investigate the effect of the natural genetic polymorphisms in type I promoter of C2ta on MHC- II expression and function. We demonstrate that an allelic variant in the type I promoter of C2ta resulted in an increased expression of MHC- II on macrophages (72-151% higher mean florescence intensity) and conventional dendritic cells (13-65% higher mean florescence intensity) in both spleen and peripheral blood. The increase in MHC- II expression resulted in an increase in antigen presentation to T cells in vitro and increased T-cell activation. The differential MHC- II expression in B6Q. C2ta, however, did not alter the disease development in models of rheumatoid arthritis (collagen-induced arthritis and human glucose-6-phosphate-isomerase325-339-peptide-induced arthritis), or multiple sclerosis ( MOG1-125 protein-induced and MOG79-96 peptide-induced experimental autoimmune encephalomyelitis). This is the first study to address the role of an allelic variant in type I promoter of C2ta in MHC- II expression and autoimmune diseases; and shows that C2ta polymorphisms regulate MHC- II expression and T-cell responses but do not necessarily have a strong impact on autoimmune diseases. [ABSTRACT FROM AUTHOR]

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) -mediated regulation of already tolerized autoreactive T cells is critical for understanding autoimmune responses. Although defects in CTLA-4 contribute to abnormal FOXP3 + regulatory T (Treg) cell function in rheumatoid arthritis, its role in autoreactive T cells remains elusive. We studied immunity towards the dominant collagen type II (CII) T-cell epitope in collagen-induced arthritis both in the heterologous setting and in the autologous setting where CII is mutated at position E266D in mouse cartilage. CTLA-4 regulated all stages of arthritis, including the chronic phase, and affected the priming of autologous but not heterologous CII-reactive T cells. CTLA-4 expression by both conventional T (Tconv) cells and Treg cells was required but while Tconv cell expression was needed to control the priming of naive autoreactive T cells, CTLA-4 on Treg cells prevented the inflammatory tissue attack. This identifies a cell-type-specific time window when CTLA-4-mediated tolerance is most powerful, which has important implications for clinical therapy with immune modulatory drugs., (© 2017 John Wiley & Sons Ltd.)