Differential Roles of IL-2 Signaling in Developing versus Mature Tregs.

Although Foxp3+ regulatory T cells (Tregs) require interleukin-2 (IL-2) for their development, it has been unclear whether continuing IL-2 signals are needed to maintain lineage stability, survival, and suppressor function in mature Tregs. We generated mice in which CD25, the main ligand-binding subunit of the IL-2 receptor, can be inducibly deleted from Tregs after thymic development. In contrast to Treg development, we find that IL-2 is dispensable for maintaining lineage stability in mature Tregs. Although continuous IL-2 signaling is needed for long-term Treg survival, CD25-deleted Tregs may persist for several weeks in vivo using IL-7. We also observe defects in glycolytic metabolism and suppressor function following CD25 deletion. Thus, unlike developing Tregs in which the primary role of IL-2 is to initiate Foxp3 expression, mature Tregs require continuous IL-2 signaling to maintain survival and suppressor function, but not to maintain lineage stability.

Immunometabolism and PI(3)K Signaling As a Link between IL-2, Foxp3 Expression, and Suppressor Function in Regulatory T Cells.

CD4+ Foxp3+ regulatory T cells (Tregs) are an essential component of immune homeostasis. Modulation of Treg function has been proposed as a means of treating autoimmune conditions and preventing rejection of organ transplants, although achieving this goal will require a detailed understanding of Treg signaling pathways. Signaling within Tregs is known to differ considerably from that observed in other T cell subsets. Of note, Tregs are the only cell type known to constitutively express CD25, the main ligand-binding subunit of the IL-2 receptor. The PI(3)K/Akt/mTOR cascade constitutes a major signaling pathway downstream of IL-2 and is closely tied to cellular metabolism. Due to increasing recognition of the links between cellular fuel usage and immune cell function, the interplay between IL-2 signaling and Treg metabolism represents an important space for exploration and a potential approach for immunomodulation. Here, we discuss how IL-2 may affect Treg metabolism via PI(3)K signaling, as well as the effects of altered metabolism on Treg lineage stability and suppressor function.

Requirement for CD28 in Effector Regulatory T Cell Differentiation, CCR6 Induction, and Skin Homing.

The skin, similar to most nonlymphoid tissues, contains substantial numbers of T cells. Among these, memory T cells serve a sentinel role to protect against pathogens, and regulatory T cells (Tregs) terminate immune responses as a check against unrestrained inflammation. Previously, we created conditional knockout mice with Treg-specific deletion of CD28. Although these mice have normal numbers of Tregs, these cells have lower levels of CTLA-4, PD-1, and CCR6, and the animals develop systemic autoimmunity characterized by prominent skin inflammation. In this study, we have performed a detailed analysis of the skin disease in these mice. Our data show that Treg-expressed CD28 is required for optimal maturation of CD44(lo)CD62L(hi) central Tregs into CD44(hi)CD62L(lo) effector Tregs (eTregs), as well as induction of CCR6 among the cells that do become eTregs. Although CD28-deficient Tregs are able to regulate inflammation normally when injected directly into the skin, they fail to home properly to inflamed skin. Collectively, these results suggest a key role for CD28 costimulation in promoting a central Treg to eTreg transition with appropriate upregulation of chemokine receptors such as CCR6 that are required for tissue homing.