CD40/CD40L interaction regulates CD4+CD25+ T reg homeostasis through dendritic cell‐produced IL‐2

CD4+CD25+ regulatory T cells (T reg) development and homeostasis require IL‐2 and costimulation through same TNF‐receptor family members. CD40KO mice have reduced number of T reg in peripheral blood, thymus and spleen. Herein we show that naive T reg express low basal level of CD40L that is upregulated upon TCR‐triggered mediated activation. Treatment of wt mice with Ab blocking CD40/CD40L interaction results in a fast decrease in T reg number that rapidly recovers upon Ab withdrawal. CFSE‐labeled T reg from wt mice injected into CD40KO, but not wild‐type (wt) mice, showed reduced survival and proliferation in homeostatic setting. In vitro, dendritic cells from CD40KO mice but not wt mice produce diminished amount of IL‐2 upon T reg encounter and are impaired in expanding T reg, a defect corrected by the addition of rIL‐2. Accordingly, four daily IL‐2 administrations to CD40KO mice normalize T reg number by promoting both their survival and homeostatic proliferation. Such IL‐2 effect is transient since T reg number returns to the low constitutive level described in CD40KO mice within 5 days upon IL‐2 withdrawal thus suggesting that IL‐2 is persistently needed to assure T reg homeostasis.