T cell activation by Coxsackievirus B4 antigens in type 1 diabetes mellitus: Evidence for selective TCR v beta usage without superantigenic activity

Numerous clinical and epidemiological studies link enteroviruses such as th e Coxsackie virus group with the autoimmune disease type I diabetes mellitu s (DM). In addition, there are reports that patients with type I DM are cha racterized by skewing of TCR V beta chain selection among peripheral blood and intraislet T lymphocytes. To examine these issues, we analyzed TCR V be ta chain-specific up-regulation of the early T cell activation marker, CD69 , on CD4 T cells after incubation with Coxsackievirus B4 (CVB4) Ags. CD4 T cells bearing the V beta chains 2, 7, and 8 were the most frequently activa ted by CVB4. Up-regulation of CD69 by different TCR families was significan tly more frequent in new onset type I DM patients (p = 0.04), 100% of whom (n = 8) showed activation of CD4 T cells bearing V beta8, compared with 50% of control subjects (n = 8; p 0.04). T cell proliferation after incubation with CVB4 Ags required live, nonfixed APCs, suggesting that the selective expansion of CD4 T cells with particular V beta chains resulted from conven tional antigen processing and presentation rather than superantigen activit y. Heteroduplex analysis of TCR V beta chain usage after CVB4 stimulation i ndicated a relatively polyclonal, rather than oligo- or monoclonal response to viral Ags. These results provide evidence that new-onset patients with type I DM and healthy controls are primed against CVB4, and that CD4 T cell responses to the virus have a selective TCR V beta chain usage which is dr iven by viral Ags rather than a superantigen.