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-alpha (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.
Rajagopalan
Govindarajan
G
Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. rajagopalan.govindarajan@mayo.edu
Mangalam
Ashutosh K
AK
Sen
Moon M
MM
Kudva
Yogish C
YC
David
Chella S
CS
D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007328:Insulin / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000276:immunology; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
D018122:B7-1 Antigen; D000949:Histocompatibility Antigens Class II; D007328:Insulin; D014409:Tumor Necrosis Factor-alpha