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) Determining a cut-off value for assigning positive and negative ELIS...
(a) Determining a cut-off value for assigning positive and negative ELISPOT responses. Graph represents a ROC plot showing assay diagnostic sensitivity (proportion of true positive tests) against specificity (one minus proportion of false positives) following detection of IFN-γ ELISPOT responses to IA-2 and PI peptides in 36 patients with T1DM and 14 nondiabetic control subjects. For each of various possible cut-off values, the sensitivity (proportion of T1DM cases positive) is plotted against one minus specificity representing the proportion of controls that are positive. SIs were calculated as the ratio of the mean response in the presence of peptide to the mean response in the presence of diluent alone. By convention, we selected the cut-off value that provides an operating position nearest to that of the “perfect test” (i.e., closest approximation to 100% sensitivity and 100% specificity), which was SI ≥ 3.0. (b–g) Representative cytokine ELISPOT responses. (b) Representative strong IFN-γ response to IA-2 peptide compared with background response to (c) diluent alone in a patient with T1DM; (d) representative moderate IFN-γ response to PI peptide compared with background response to (e) diluent alone in a patient with T1DM; (f) representative IL-10 response to IA-2 peptide compared with background response to (g) diluent alone in a non-diabetic control subject.