Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis

Abstract

The major known genetic risk factors in multiple sclerosis reside in the major histocompatibility complex (MHC) region. Although there is strong evidence implicating MHC class II alleles and CD4(+) T cells in multiple sclerosis pathogenesis, possible contributions from MHC class I genes and CD8(+) T cells are controversial. We have generated humanized mice expressing the multiple sclerosis-associated MHC class I alleles HLA-A(*)0301 (encoding human leukocyte antigen-A3 (HLA-A3)) and HLA-A(*)0201 (encoding HLA-A2) and a myelin-specific autoreactive T cell receptor (TCR) derived from a CD8(+) T cell clone from an individual with multiple sclerosis to study mechanisms of disease susceptibility. We demonstrate roles for HLA-A3-restricted CD8(+) T cells in induction of multiple sclerosis-like disease and for CD4(+) T cells in its progression, and we also define a possible mechanism for HLA-A(*)0201-mediated protection. To our knowledge, these data provide the first direct evidence incriminating MHC class I genes and CD8(+) T cells in the pathogenesis of human multiple sclerosis and reveal a network of MHC interactions that shape the risk of multiple sclerosis.

HLA-class I markers and multiple sclerosis susceptibility in the Italian population

“…On the other hand, evidence reported in this study and from work undertaken using an experimental animal model 17 points to a direct role of A*02. In our study, A*02 was also significantly protective in the absence of Cw*05 (OR ¼ 0.73, Po10 À4 ).…”

“…Thus, an effect of A*02 alone cannot be excluded. Moreover, Friese et al 17 recently reported that the MS-like disease developed by double transgenic mice expressing both a human HLA-class I allele (A*03) and a human myelin-specific autoreactive T-cell receptor is completely prevented by further adding an HLA-A*0201 transgene. Thus, A*02, which protects against MS in human populations, also prevents an MS-like disease in transgenic humanized mice.…”

“…This protection resulted from thymic deletion of autoreactive T cells, which greatly reduced their number in the periphery. 17 Both HLA-A and -C genes are interesting candidates for a direct role in MS pathogenesis, as their encoded molecules present antigenic peptides and interact with NK receptors. 18,19 However, several other genes in this region might be primarily associated with MS.…”

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

“…PLP [45][46][47][48][49][50][51][52][53] immunization in complete Freund adjuvant induces mild disease in 71% of these mice, followed in 25% of them by a severe disease leading to hind limb paralysis. The PLP [45][46][47][48][49][50][51][52][53] -specific CD8 T cells mediate the first phase of this disease, whereas the second phase is due to CD4 T cells targeting the MOG epitope in the context of the murine I-A b molecule [66]. Therefore, this study demonstrates that CD8-driven autoimmune demyelination can initiate epitope spreading.…”

Multiple sclerosis associates with LILRA3 deletion in Spanish patients

“…22,25 Best known among pathogens that tamper major histocompatibility complex class I expression are herpesviruses, which can alter T-and natural killer-lymphocyte function by subverting the expression of host major histocompatibility complex molecules, or by encoding viral homologues of these. [26][27][28][29][30][31] As all of the polymorphisms of the LRC in chromosome 19, natural killer cells, herpesviruses and HLA class I molecules have been implicated in the susceptibility or pathogenesis of MS, 8,[32][33][34][35][36][37][38][39] it is also of interest to determine whether the genotypic diversity of KIR is associated with MS and whether such an association could explain, by linkage disequilibrium (LD), the reported relationship between MS and deletion of LILRA3.…”