Regulation of naturally-occurring CD4+CD25+ regulatory T cell development by E3 ubiquitin ligase Cbl-b (P1041)

Abstract

Abstract Naturally-occurring CD4+CD25+Foxp3+ regulatory T cells ("nTregs") are involved in shutting down immune responses after they have successfully eliminated invading organisms, and also in preventing autoimmunity. CD28 costimulation is essential for the development of nTregs in thymus. E3 ubiquitin ligase Cbl-b has been shown to regulate CD28 dependence of T cell activation. Here, we report that the loss of Cbl-b partially but significantly rescues the defective development of nTregs in CD28-/- mice. This partial rescue is likely to be independent of IL-2 because treating CD28-/- mice with IL-2/anti-IL-2 complex, which has been shown to selectively stimulate nTregs, fails to rescue defective development of CD4+CD8-CD25+Foxp3+ nTregs in thymuses of CD28-/- mice. Mechanistically, Cbl-b binds to Foxp3 upon TCR stimulation, and targets Foxp3 for ubiquitination and subsequently degradation in the proteasome. As Cbl-b self-ubiquitination and proteasomal degradation is impaired in CD28-/- T cells, the defective development of nTregs in CD28-/- mice may in part be due to increased Foxp3 ubiquitination and degradation targeted by Cbl-b. Therefore, we provide a previously-unappreciated function for Cbl-b in regulating Foxp3 expression via an ubiquitination-dependent mechanism.