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T Cell Activation by Coxsackievirus B4 Antigens in Type 1 Diabetes Mellitus: Evidence for Selective TCR V Usage Without Superantigenic Activity¹

Ruben Varela-Calvino^*, Gianluca Sgarbi^*, Lucy R. Wedderburn, Colin M. Dayan, Jenny Tremble^* and Mark Peakman^2,*

^* Department of Immunology, Guy’s, King’s and St. Thomas’ School of Medicine, London, United Kingdom; Rheumatology Unit, Institute of Child Health, UCL, London, United Kingdom; and Division of Medicine, University of Bristol, Bristol, United Kingdom

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 V chain selection among peripheral blood and intraislet T lymphocytes. To examine these issues, we analyzed TCR V 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 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 V8, 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 chains resulted from conventional antigen processing and presentation rather than superantigen activity. Heteroduplex analysis of TCR V 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 V chain usage which is driven by viral Ags rather than a superantigen.

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				R. Varela-Calvino, A. Skowera, S. Arif, and M. Peakman Identification of a Naturally Processed Cytotoxic CD8 T-Cell Epitope of Coxsackievirus B4, Presented by HLA-A2.1 and Located in the PEVKEK Region of the P2C Nonstructural Protein J. Virol., December 15, 2004; 78(24): 13399 - 13408. [Abstract] [Full Text] [PDF]

				R. Varela-Calvino, R. Ellis, G. Sgarbi, C. M. Dayan, and M. Peakman Characterization of the T-Cell Response to Coxsackievirus B4: Evidence That Effector Memory Cells Predominate in Patients With Type 1 Diabetes Diabetes, June 1, 2002; 51(6): 1745 - 1753. [Abstract] [Full Text] [PDF]