GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes
Vissia Viglietta, … , Tihamer Orban, David A. Hafler
Vissia Viglietta, … , Tihamer Orban, David A. Hafler
Published April 1, 2002
Citation Information: J Clin Invest. 2002;109(7):895-903. https://doi.org/10.1172/JCI14114.
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Article Immunology

GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes

Abstract

Insulin-dependent type 1 diabetes is an autoimmune disease mediated by T lymphocytes recognizing pancreatic islet cell antigens. Glutamic acid decarboxylase 65 (GAD65) appears to be an important autoantigen in the disease. However, T cells from both patients with type 1 diabetes and healthy subjects vigorously proliferate in response to GAD65 stimulation ex vivo, leading us to postulate that the critical event in the onset of human diabetes is the activation of autoreactive T cells. Thus, we investigated whether GAD65-reactive T cells in patients with diabetes functioned as previously activated memory T cells, no longer requiring a second, costimulatory signal for clonal expansion. We found that in patients with new-onset type 1 diabetes, GAD65-reactive T cells were strikingly less dependent on CD28 and B7-1 costimulation to enter into cell cycle and proliferate than were equivalent cells derived from healthy controls. We hypothesize that these autoreactive T cells have been activated in vivo and have differentiated into memory cells, suggesting a pathogenic role in type 1 diabetes. In addition, we observed different effects with selective blockade of either B7-1 or B7-2 molecules; B7-1 appears to deliver a negative signal by engaging CTLA-4, while B7-2 engagement of CD28 upregulates T cell proliferation and cytokine secretion.

Authors

Vissia Viglietta, Sally C. Kent, Tihamer Orban, David A. Hafler

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Proliferative response to GAD65 is not dependent on CD28/B7 co-stimulato...
Proliferative response to GAD65 is not dependent on CD28/B7 co-stimulatory pathway in type 1 diabetes patients. The mean percentage of inhibition of GAD65-specific proliferation and cytokine secretion with CD28 blockade, as described in Figure 1, is shown. Each symbol is representative of ten diabetic patients (open circles) or nine normal controls (filled circles). The Mann-Whitney test was used to estimate the difference in the CD28 requirement between diabetic patients and controls. The difference between the two groups was significant at any concentration of GAD65 (diabetic patients vs. controls, proliferation: GAD, 5 μg/ml and 10 μg/ml, P = 0.0019; GAD 20 μg/ml, P = 0.0047; IFN-γ: GAD 5 μg/ml, P = 0.049; GAD 10 μg/ml, P = 0.0019; GAD 20 μg/ml, P = 0.001; IL-13: GAD 5 μg/ml, P = 0.049; GAD 10 μg/ml, P = 0.03; GAD 20 μg/ml, P = 0.0019) showing that antigen-specific T cells from type 1 diabetes patients are CD28 independent. No inhibition was detected in TT-specific T cells at any concentration of antigen either in the patients or in the normal controls.