Role of MHC class II expressing CD4⁺ T cells in proteolipid protein_91–110‐induced EAE in HLA‐DR3 transgenic mice

Abstract

MHC class II molecules play a central role in the control of adaptive immune responses through selection of the CD4(+) T cell repertoire in the thymus and antigen presentation in the periphery. Inherited susceptibility to autoimmune disorders such as multiple sclerosis, rheumatoid arthritis and IDDM are associated with particular MHC class II alleles. Advent of HLA transgenic mice has helped us in deciphering the role of particular HLA DR and DQ class II molecules in human autoimmune diseases. In mice, the expression of class II is restricted to professional antigen-presenting cells (APC). However, in humans, class II is also expressed on T cells, unlike murine T cells. We have developed new humanized HLA class II transgenic mice expressing class II molecules not only on APC but also on a subset of CD4(+) T cells. The expression of class II on CD4(+) T cells is inducible, and class II(+) CD4(+) T cells can present antigen in the absence of APC. Further, using EAE, a well-established animal model of MS, we tested the functional significance of these class II(+) CD4(+) T cells. DR3.AEo transgenic mice were susceptible to proteolipid protein(91-110)-induced EAE and showed CNS pathology accompanied by widespread inflammation and demyelination seen in human MS patients, suggesting a role for class II(+) CD4(+) T cells in the pathogenesis.

Gender-Biased Regulation of Human IL-17-Producing Cells <i>in Vitro</i> by Peptides Corresponding to Distinct <i>HLA-DRB</i>1 Allele-Coded Sequences

“…Additionally, mice do not have an exact match for SE sequence (21, 31, 32). Strikingly, transgenic mice engineered to express SE-positive HLA class II molecules are more prone to inflammatory and autoimmune diseases than non-transgenic mice (33). Additionally, a higher level of expression of MHC class II lymphocytes from synovial fluid of RA patients than healthy donors has been described as well (34).…”

Spontaneous lupus-like syndrome in HLA-DQ2 transgenic mice with a mixed genetic background

“…A principal finding that supports the particular role of DQ2 gene in disease development is the absence of disease in the DQ6 transgenic mice that had the same knockout background (AE°) as the DQ2 transgenic mice. The absence of spontaneous lupus-like disease in AE°DR3 mice42 is also suggestive of an independent role of DQ2 genes in the development of this disease.…”

The Impact ofStaphylococcus aureus-Associated Molecular Patterns on Staphylococcal Superantigen-Induced Toxic Shock Syndrome and Pneumonia

“…In a similar manner, in addition to the conventional APCs, MHC class II (HLA-DR3) molecules are also expressed on activated T cells in our transgenic mice, as shown by RT-PCR and flow cytometry. T cells from HLA-DR3 transgenic mice can present antigens and SSAg to other T cells [44]. Thus, HLA class II molecules are widely expressed by several professional and nonprofessional APCs.…”