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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Reproducibility of cytokine ELISPOT analyses. (a) Intra-assay variabilit...
Reproducibility of cytokine ELISPOT analyses. (a) Intra-assay variability. The same PBMC preparation has been analyzed 12 times on the same sample plate. IFN-γ spot number per well (300,000 cells) is shown for medium and in the presence of 100 ng/ml tetanus toxoid. The intra-assay coefficient of variation for the 12 repeated analyses is 12.3%. (b) Inter-assay variability. The same donor has been venesected on seven separate occasions. IFN-γ spot number per well (300,000 cells) is shown for medium (black bars) and in the presence of 100 ng/ml tetanus toxoid (white bars) for each time point 1–7, representing (time point 1) November 2002, (time points 2–4) three occasions in August 2003, and (time points 5–7) three occasions in September 2003. The interassay coefficient of variation for the seven repeated analyses is 10.2%.