ICOS-dependent homeostasis and function of Foxp3+ regulatory T cells in islets of nonobese diabetic mice

M Kornete, E Sgouroudis, CA Piccirillo - The Journal of Immunology, 2012 - journals.aai.org
M Kornete, E Sgouroudis, CA Piccirillo
The Journal of Immunology, 2012journals.aai.org
A progressive waning in Foxp3+ regulatory T cell (Treg) functions is thought to provoke
autoimmunity in the NOD model of type 1 diabetes (T1D). A deficiency in IL-2 is one of the
main triggers for the defective function of Tregs in islets. Notably, abrogation of the ICOS
pathway in NOD neonates or BDC2. 5-NOD (BDC2. 5) mice exacerbates T1D, suggesting
an important role for this costimulatory pathway in tolerance to islet Ags. Thus, we
hypothesize that ICOS selectively promotes Foxp3+ Treg functions in BDC2. 5 mice. We …
Abstract
A progressive waning in Foxp3+ regulatory T cell (Treg) functions is thought to provoke autoimmunity in the NOD model of type 1 diabetes (T1D). A deficiency in IL-2 is one of the main triggers for the defective function of Tregs in islets. Notably, abrogation of the ICOS pathway in NOD neonates or BDC2. 5-NOD (BDC2. 5) mice exacerbates T1D, suggesting an important role for this costimulatory pathway in tolerance to islet Ags. Thus, we hypothesize that ICOS selectively promotes Foxp3+ Treg functions in BDC2. 5 mice. We show that ICOS expression discriminates effector Foxp3− T cells from Foxp3+ Tregs and specifically designates a dominant subset of intra-islet Tregs, endowed with an increased potential to expand, secrete IL-10, and mediate suppressive activity in vitro and in vivo. Consistently, Ab-mediated blockade or genetic deficiency of ICOS selectively abrogates Treg-mediated functions and T1D protection and exacerbates disease in BDC2. 5 mice. Moreover, T1D progression in BDC2. 5 mice is associated with a decline in ICOS expression in and expansion and suppression by intra-islet Foxp3+ Tregs. We further show that the ICOS+ Tregs, in contrast to their ICOS− counterparts, are more sensitive to IL-2, a critical signal for their survival and functional stability. Lastly, the temporal loss in ICOS+ Tregs is readily corrected by IL-2 therapy or protective Il2 gene variation. Overall, ICOS is critical for the homeostasis and functional stability of Foxp3+ Tregs in prediabetic islets and maintenance of T1D protection.
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