Requirement for CD28 in Effector Treg Differentiation, CCR6 induction, and Skin Homing

Abstract

The skin, like most non-lymphoid tissues, contains substantial numbers of T cells. Among these, memory T cells serve a sentinel role to protect against pathogens, and regulatory T cells 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. Here, 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 ^loCD62L ^hi central Tregs (cTreg) into CD44 ^hiCD62L ^lo effector Tregs (eTregs), and induction of CCR6 among the cells that do become eTregs. While 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 cTreg to eTreg transition with appropriate upregulation of appropriate chemokine receptors such as CCR6 that are required for tissue homing.