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

Abstract

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.

• HLA-DQ8
• transgenic mice
• MHC
• NOD

Acknowledgements

We thank Julie Hanson and her crew for excellent mice husbandry, and Michelle Smart for characterizing the transgenic mice. We also acknowledge Li Wen and Richard Flavell (Yale University, New Haven, CT) for providing the RIP.B7 and RIP.TNF transgenic mice, respectively. Financial support from American Diabetes Association to CSD is also acknowledged. GR is a recipient of Juvenile Diabetes Research Foundation International fellowship award (2004–2006).