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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Cytokine ELISPOT responses to islet peptides are mediated by CD4 T cells...
Cytokine ELISPOT responses to islet peptides are mediated by CD4 T cells. (a and b) Representative analyses from two T1DM patients positive (SI > 3.0) for IFN-γ responses to the IA-2 peptides 709–735 (triangles), 752–775 (squares), and PI peptide C19-A3 (circles), in which peptides were cultured with entire PBMCs or PBMCs immunomagnetically depleted of CD4 T cells before the ELISPOT analysis. (a) Background (medium alone) responses for the patients were 5.3 ± 1.9 spots per well (mean ± SEM) and (b) 1.3 ± 0.6 spots per well. In both subjects positive responses are reduced to background levels by CD4 depletion.