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

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 β 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.

特定的主要组织相容性复合体（major histocompatibility complex, MHC）II类等位基因，在人类与非肥胖糖尿病（nonobese diabetic, NOD）小鼠中均明确参与T细胞介导的自身免疫性1型糖尿病（type 1 diabetes, T1D）的致病进程。然而针对NOD小鼠的研究表明，MHC I类分子限制性T细胞应答同样对T1D的发生至关重要。在人类群体中，流行病学研究提示，部分常见的I类等位基因（包括HLA-A2.1 (A*02011)）若与特定II类等位基因共同表达，可能会增加个体罹患T1D的易感性。本研究证实，当HLA-A2.1分子在NOD小鼠体内转基因表达时，会产生针对胰腺β细胞的A2限制性T细胞应答，进而导致T1D发病提前。NOD.HLA-A2.1转基因小鼠的T1D发病加速现象，并非由表达第三种I类分子所带来的非特异性效应所致——因为另一批转基因表达HLA-B27 I类分子的NOD小鼠，不仅未出现T1D发病加速的情况，反而显著抵御了该疾病的发生。上述发现首次提供了功能性证据，证明特定人类MHC I类分子可参与T1D的致病进程。