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

S Arif, TI Tree, TP Astill, JM Tremble… - The Journal of …, 2004 - Am Soc Clin Investig
S Arif, TI Tree, TP Astill, JM Tremble, AJ Bishop, CM Dayan, BO Roep, M Peakman
The Journal of clinical investigation, 2004Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation