AbstractWhile it is generally accepted that T cells are critical for the development of diabetes in the non‐obese diabetic (NOD) mouse, the precise functions of the CD4+and CD8+subsets remain ill‐defined. Transfer experiments have provided evidence that CD4+cells are the disease initiators, provoking massive mononuclear leukocyte infiltration into the pancreatic islets, while CD8+cells play an effector role, responsible for the final destruction of islet beta cells. It was surprising, then, to find that NOD mice carrying a null mutation at the β2‐microglobulin (β2‐μ) locus, and thereby lacking major histocompatibility complex class I molecules and CD8+T cells, developed neither insulitis nor diabetes. Here, we argue that the absence of insulitis in these animals results from their lack of CD8+cells because islet infiltration is also absent when NOD mice are treated with an anti‐CD8 monoclonal antibody (mAb) at a young age. Interestingly, the anti‐CD8 effect is only observed when the mAb is injected during a discrete age window – 2 to 5 weeks after birth. Transfer experiments indicate that the lack of CD8+cells during this period somehow alters the phenotype of CD4+cells, preventing them from expressing their insulitic potential. This is not because they are generally immuno‐incompetent nor because they are generally more prone to differentiating into cells with Th2 characteristics. Given that neither the β2‐μ mutation nor anti‐CD8 treatment affect insulitis in a T cell receptor transgenic (tg) mouse strain with a CD4+T cell repertoire highly skewed for an anti‐islet cell reactivity, the most straight‐forward interpretation of these observations is that CD8+cells are required for effective priming and expansi
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