T-cell tolerance and the multi-functional role of IL-2R signaling in T-regulatory cells

Abstract

Signaling through the interleukin-2 receptor (IL-2R) contributes to T-cell tolerance by controlling three important aspects of regulatory T-cell (Treg) biology. IL-2 is essential for thymic Treg development and regulates Treg homeostasis and suppressive function. Analogous to activated conventional T lymphocytes, IL-2R signaling also plays an important part in Treg cell growth, survival, and effector differentiation. However, Treg cells somewhat distinctively assimilate IL-2R signaling. In particular, Treg cells require essentially only IL-2-dependent receptor proximal signal transducer and activator of transcription 5 (Stat5) activation, as they contain inhibitory pathways to minimize IL-2R-dependent activation of the phosphatidyinositol 3-kinase/Akt pathway. Moreover, many IL-2R-dependent activities, including full induction of Foxp3 expression, in Treg cells require minimal and transient Stat5 activation. Thus, Treg cells are equipped to sense and then develop and function within biological niches containing minimal IL-2. These distinguishing features of IL-2R signaling provide a mechanistic underpinning for using IL-2 as an agent to selectively target Treg cells in immunotherapy to induce tolerance in autoimmune diseases and in allogeneic transplant recipients.

© 2011 John Wiley & Sons A/S.

Figures

Fig. 1. Transgenic IL-2Rβ mutants and their effect on autoimmunity and Treg development after expression in IL-2Rβ−/− mice

Fig. 2. Treg cells that express IL-2Rβ lacking both the A- and H-regions (ΔAH) do not activate STAT5

Fig.3. Varied levels of IL-2R signaling strength support distinct functional activities of nTreg cells

Thymus and lymph node cells from mice of the indicated IL-2Rβ genotype (2Rβ) were rested for 30 min in medium and then stimulated with IL-2 (10 ng/ml) for the indicated time. Activation of tyrosine-phosphorylated STAT5 (pSTAT5) was determined by flow cytometry after gating on CD4+Foxp3+ T cells. Data were normalized to the maximal response by control 2Rβ+/− Treg cells. Data represent 2-3 mice/group.