Biotin
Antigen presentation by the MHC-II to CD4+ T cells is important in adaptive immune responses. The class II transactivator (CIITA in human and C2TA 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.
Rift Valley fever virus (RVFV) is an arbovirus that causes disease in livestock and humans in Africa and the Middle East. While human disease is typically mild and self-limiting, some individuals develop severe manifestations, such as hepatitis, hemorrhagic fever, or encephalitis. Encephalitis occurs 2 to 3 weeks after acute illness; therefore, we hypothesized that it was a result of an inadequate adaptive immunity. To test this hypothesis in vivo, we used an attenuated virus (DelNSsRVFV) that does not typically cause disease in mice. We first characterized the normal immune response to infection with DelNSsRVFV in immunocompetent mice and noted expansion of natural killer cells and monocytes, as well as activation of both CD8 and CD4 T cells. Depleting C57BL/6 mice of CD4 T cells prior to DelNSsRVFV infection resulted in encephalitis in 30% of the mice; in encephalitic mice, we noted infiltration of T cells and inflammatory monocytes into the brain. CD4 and CD8 codepletion in C57BL/6 mice, as well as CD4 depletion in CCR2 knockout mice, increased the frequency of encephalitis, demonstrating that these cell types normally contributed to the prevention of disease. Encephalitic mice had similar viral RNA loads in the brain regardless of which cell types were depleted, suggesting that CD4 T cells, CD8 T cells, and inflammatory monocytes did little to control viral replication in the brain. CD4-depleted mice exhibited diminished humoral and T cell memory responses, suggesting that these immune mechanisms contributed to peripheral control of virus, thus preventing infection of the brain.IMPORTANCE RVFV is found in Africa and the Middle East and is transmitted by mosquitos or through contact with infected animals. Infected individuals can develop mild disease or more severe forms, such as hepatitis or encephalitis. In order to understand why some individuals develop encephalitis, we first need to know which immune functions protect those who do not develop this form of disease. In this study, we used a mouse model of RVFV infection to demonstrate that CD4 T cells, CD8 T cells, and monocytes all contribute to prevention of encephalitis. Their likely mechanism of action is preventing RVFV from ever reaching the brain.
