T cell activation by coxsackievirus B4 antigens in type 1 diabetes mellitus: evidence for selective TCR Vbeta usage without superantigenic activity

• Published in: The Journal of immunology (1950) 2001-09, Vol.167 (6), p.3513-3520
• Main Authors: Varela-Calvino, R, Sgarbi, G, Wedderburn, L R, Dayan, C M, Tremble, J, Peakman, M
• Format: Article
• Language: English
• Subjects: Adult; Antigen Presentation; Antigen-Presenting Cells - immunology; Antigens, CD - biosynthesis; Antigens, CD - genetics; Antigens, Differentiation, T-Lymphocyte - biosynthesis; Antigens, Differentiation, T-Lymphocyte - genetics; Antigens, Viral - immunology; Autoimmune Diseases - etiology; Autoimmune Diseases - immunology; CD4-Positive T-Lymphocytes - immunology; Cell Division; Coculture Techniques; Diabetes Mellitus, Type 1 - etiology; Diabetes Mellitus, Type 1 - immunology; Enterovirus B, Human - immunology; Enterovirus B, Human - pathogenicity; Enterovirus Infections - complications; Enterovirus Infections - immunology; Enterovirus Infections - virology; Female; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; Heteroduplex Analysis; Humans; Lectins, C-Type; Lymphocyte Activation; Male; Receptors, Antigen, T-Cell, alpha-beta - genetics; Superantigens - immunology; T-Lymphocyte Subsets - immunology; Up-Regulation
• ISSN: 0022-1767

Numerous clinical and epidemiological studies link enteroviruses such as the Coxsackie virus group with the autoimmune disease type 1 diabetes mellitus (DM). In addition, there are reports that patients with type 1 DM are characterized by skewing of TCR Vbeta chain selection among peripheral blood and intraislet T lymphocytes. To examine these issues, we analyzed TCR Vbeta 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 Vbeta chains 2, 7, and 8 were the most frequently activated by CVB4. Up-regulation of CD69 by different TCR families was significantly more frequent in new onset type 1 DM patients (p = 0.04), 100% of whom (n = 8) showed activation of CD4 T cells bearing Vbeta8, 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 Vbeta chains resulted from conventional antigen processing and presentation rather than superantigen activity. Heteroduplex analysis of TCR Vbeta chain usage after CVB4 stimulation indicated a relatively polyclonal, rather than oligo- or monoclonal response to viral Ags. These results provide evidence that new-onset patients with type 1 DM and healthy controls are primed against CVB4, and that CD4 T cell responses to the virus have a selective TCR Vbeta chain usage which is driven by viral Ags rather than a superantigen.