T cell activation by coxsackievirus B4 antigens in type 1 diabetes mellitus: evidence for selective TCR Vbeta usage without superantigenic activity.
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.
Varela-Calvino
R
R
Department of Immunology, Guy's, King's and St. Thomas' School of Medicine, London, United Kingdom.
Sgarbi
G
G
Wedderburn
L R
LR
Dayan
C M
CM
Tremble
J
J
Peakman
M
M
D000328:Adult; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D000956:Antigens, Viral / Q000276:immunology*; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002455:Cell Division; D018920:Coculture Techniques; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology*; D029822:Enterovirus B, Human / Q000276:immunology* / Q000472:pathogenicity; D004769:Enterovirus Infections / Q000150:complications / Q000276:immunology* / Q000821:virology; D005260:Female; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D020180:Heteroduplex Analysis; D006801:Humans; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D008297:Male; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D018089:Superantigens / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D015854:Up-Regulation; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000956:Antigens, Viral; D037181:Lectins, C-Type; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens; D000099192:CD69 Antigens