Functional evidence for the mediation of diabetogenic T cell responses by HLA-A2.1 MHC class I molecules through transgenic expression in NOD mice

Abstract

Particular major histocompatibility complex (MHC) class II alleles clearly contribute to T cell-mediated autoimmune type 1 diabetes (T1D) in both humans and nonobese diabetic (NOD) mice. However, studies in NOD mice indicate MHC class I-restricted T cell responses are also essential to T1D development. In humans, epidemiological studies have suggested that some common class I alleles, including HLA-A2.1 (A*02011), may confer increased susceptibility to T1D when expressed in conjunction with certain class II alleles. We show here that when HLA-A2.1 molecules are transgenically expressed in NOD mice, A2-restricted T cell responses arise against pancreatic ␤ cells, leading to an earlier onset of T1D. The accelerated onset of T1D in the NOD.HLA-A2.1 transgenic mice is not due to nonspecific effects of expressing a third class I molecule, because a stock of NOD mice transgenically expressing HLA-B27 class I molecules showed no such acceleration of T1D, but rather were significantly protected from disease. These findings provide the first functional evidence that certain human MHC class I molecules can contribute to the development of T1D.T ype 1 diabetes (T1D) in both humans and nonobese diabetic (NOD) mice is the result of T cell-mediated autoimmune destruction of insulin-secreting pancreatic ␤ cells. The immunotolerogenic defects underlying the initial development of diabetogenic T cells, as well as the events involved in their subsequent activation, are genetically controlled by multiple susceptibility (Idd) alleles both within and outside of the major histocompatibility complex (MHC) (1, 2). Although T1D is a complex disorder involving interaction of multiple susceptibility loci with unknown environmental factors, the primary genetic component of susceptibility in humans and NOD mice is provided by particular MHC haplotypes (reviewed in refs. 3-6). Within the MHC, specific combinations of HLA-DQ and -DR class II alleles provide a large component of T1D susceptibility in humans by mediating ␤ cell autoreactive CD4 T cell responses (reviewed in refs. 3 and 4). A particularly strong class II contributor to T1D in humans is the DQ8 variant characterized by histidine and serine, rather than the more common proline and aspartic acid residues at positions 56 and 57 of the ␤ chain. Similarly, transgenic analyses (7-11) have demonstrated that T1D development in NOD mice requires that the unusual H2-A g7 MHC class II gene product (homologue of human DQ8) be homozygously expressed in the absence of H2-E MHC class II molecules (homologue of human DR). However, although they represent common variants shared by many strains lacking autoimmune proclivity, the K Several studies have provided evidence that the risk of T1D development in humans is increased when certain MHC class I variants are expressed in conjunction with particular MHC class II susceptibility alleles (17-20, ‡). As in NOD mice, these putative human class I susceptibility variants include some common alleles such as HLA-A2.1 (official designation A*02011) (17,18...

Autoreactive CD8 T cells associated with β cell destruction in type 1 diabetes

“…These results provide functional evidence that the HLA-A*0201 allele contributes to type 1 diabetes development (8). The HLA-A*0201 allele has been shown to confer additional risk to the development of type 1 diabetes in patients possessing the high-risk class II alleles HLA-DR3 and HLA-DR4 (9).…”

Apportioning Blame: Autoreactive CD4+ and CD8+ T Cells in Type 1 Diabetes

“…Furthermore, in the case of the A*02:01 allele, functional in vivo data indicates that this HLA molecule is able to select cytotoxic CD8 + T cells capable of destroying insulin-producing beta cells. Transgenic expression of A*02:01 in a mouse model with a NOD genetic background shows accelerated diabetes development as compared to nontransgenic littermates (Marron et al 2002).…”

What can the HLA transgenic mouse tell us about autoimmune diabetes?

“…Whilst the HLA class I genetic association with diabetes is not as strong as with MHC class II, a number of alleles are commonly expressed in patients with diabetes [5,99]. The only in vivo study in diabetes to date has been the investigation of the effect of HLA-A2.1 as a transgene crossed on to the NOD background [100]. This HLA transgene was coexpressed with mouse MHC class I (K d D b ) and II (I-A g7 ) molecules, and an acceleration of diabetes was shown in the presence of the transgene.…”