Distinct local immunogenic stimuli dictate differential requirements for CD4⁺ and CD8⁺ T cell subsets in the pathogenesis of spontaneous autoimmune diabetes

The strong MHC class II association in human as well as murine Type 1 diabetes (T1D) suggests a central role for CD4⁺ T cells in the disease pathogenesis. Nonetheless, CD8⁺ T cells also play a role in the pathogenic process. We describe how CD4⁺ or CD8⁺ T cells can contribute differentially to the pathogenesis of T1D using the HLA-DQ8 transgenic mouse models. HLA-DQ8 transgenic mice expressing the costimulatory molecule, B7.1 (RIP.B7.1), or the proinflammatory cytokine, TNF-α (RIP.TNF) or both (RIP.B7.RIP.TNF) under the control of rat insulin promoter (RIP) were used. Our observations indicate that in the RIP-B7 model, CD4⁺ T cells were absolutely required for diabetes to occur. However, when CD8⁺ T cells were also present, the incidence of diabetes increased. On the other hand, in the RIP-TNF model, CD8⁺ T cells were absolutely required for diabetes to occur. Interestingly, when CD4⁺ T cells were also present, the incidence of diabetes decreased. In the RIP-B7.RIP-TNF double transgenic mouse model, either CD4⁺ or CD8⁺ T cells were sufficient to precipitate diabetes in 100% of the animals. Thus, the relative roles of CD4⁺ or CD8⁺ T cells in the pathogenesis of T1D are possibly determined by the local inflammatory stimuli.