Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health
Sefina Arif, … , Bart O. Roep, Mark Peakman
Sefina Arif, … , Bart O. Roep, Mark Peakman
Published February 1, 2004
Citation Information: J Clin Invest. 2004;113(3):451-463. https://doi.org/10.1172/JCI19585.
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Article Immunology

Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health

Abstract

According to the quality of response they mediate, autoreactive T cells recognizing islet β cell peptides could represent both disease effectors in the development of type 1 diabetes (T1DM) and directors of tolerance in nondiabetic individuals or those undergoing preventative immunotherapy. A combination of the rarity of these cells, inadequate technology, and poorly defined epitopes, however, has hampered examination of this paradigm. We have identified a panel of naturally processed islet epitopes by direct elution from APCs bearing HLA-DR4. Employing these epitopes in a sensitive, novel cytokine enzyme-linked immunosorbent spot assay, we show that the quality of autoreactive T cells in patients with T1DM exhibits extreme polarization toward a proinflammatory Th1 phenotype. Furthermore, we demonstrate that rather than being unresponsive, the majority of nondiabetic, HLA-matched control subjects also manifest a response against islet peptides, but one that shows extreme T regulatory cell (Treg, IL-10–secreting) bias. We conclude that development of T1DM depends on the balance of autoreactive Th1 and Treg cells, which may be open to favorable manipulation by immune intervention.

Authors

Sefina Arif, Timothy I. Tree, Thomas P. Astill, Jennifer M. Tremble, Amanda J. Bishop, Colin M. Dayan, Bart O. Roep, Mark Peakman

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(a) Polarization of autoreactive T cell responses to IA-2 and PI peptide...
(a) Polarization of autoreactive T cell responses to IA-2 and PI peptides in patients with T1DM (open circles) and nondiabetic control subjects (closed triangles). For any given positive peptide response (SI ≥ 3.0 for IFN-γ or IL-10), the SI for each cytokine has been plotted. There is a highly significant inverse correlation between responses represented by each of these cytokines (P = 0.000004), indicating extreme polarization of proinflammatory and regulatory autoreactivity. Patients with T1DM are clustered close to the y axis, and nondiabetic control subjects are distributed along the x axis, indicating the association of disease and tolerant states with proinflammatory and regulatory responses, respectively. (b) Relationship between age at onset of T1DM and production of IL-10 in response to peptides of IA-2 and PI. Of 24 patients tested, those making IL-10 responses are significantly older (P = 0.01).