Treg cell depletion in adult mice results in activation of antigen-presenting cells prior to fatal autoimmune disease

Abstract

Abstract Studies in mice expressing the diphtheria toxin receptor (DTR) exclusively on regulatory T (Treg) cells (Foxp3-DTR mice) demonstrated the critical importance of Treg cells in maintaining normal immune homeostasis. Adult Foxp3-DTR mice injected with DT begin to die from day 10 after DT treatment. Marked expansion of almost all immune cell types was observed prior to death. The purpose of the present studies was to examine in-depth changes in lymphocytes and antigen-presenting cells at early time points after Treg depletion to determine the most critical cell types controlled by Treg in the steady state. Complete depletion of Treg was observed 2 days after treatment, but profound activation of CD4 +and CD8 +T cells as measured by induction of CD44 expression and vigorous proliferation as measured by Ki-67 incorporation were not seen on day 2 but seen on day 6 of DT treatment. Curiously, most of the CD44 hiKi-67 +T cells were CD25 −and plasma levels and intracellular levels of IL-2 were not increased suggesting that early activation of CD4 +and CD8 +T cells was not the result of a burst of IL-2 production. Increased expression of CD80, CD86, CD40, and PD-L1 could be detected on CD11c +dendritic cells (DCs) on day 6. Anti-CD80/CD86 mAbs reversed the activation of T cells provoked by depletion of Treg cells, while anti-IL-2 or anti-IL-2Rb mAbs had no effect. Taken together, these studies suggest that disruption of the regulation of Treg-mediated control of DC activation represents the first step in the complex autoimmune disease seen after Treg depletion. This work was supported by the Intramural Research Program of NIAID, NIH. This work was supported by the Intramural Research Program of NIAID, NIH.