Kaili Zhong, Wengang Song, Qian Wang, Chao Wang, Xi Liu, Dongwei Chen, Zhongli Zhu, Yiqing Wu, Weijing Zhang, Minghui Zhang

The contraction phase of antigen-specific immune responses involves the apoptotic loss of numerous activated lymphocytes. While apoptotic cells are known to induce immune suppression, the mechanisms involved therein are still ambiguous. Some reports have speculated that macrophages can induce regulatory T cells (Tregs) after engulfing apoptotic cells. In this study, we showed that dendritic cells (DCs) that phagocytose apoptotic T cells acquire inhibitory function (named DCapos) toward CD4(+) and CD8(+) T cells. These inhibitory DCs could not induce the generation of Tregs, but they were found to directly inhibit mDCs that initiate CD4(+) and CD8(+) T cell proliferation both in vitro and in vivo. Soluble factors including NO play a role in the DCapos-induced suppression of CD4(+) and CD8(+) T cell proliferation. Further results showed that STAT3 phosphorylation and inducible nitric oxide synthase (iNOS) generation were enhanced when DCs were co-cultured with apoptotic cells. Both iNOS transcription and NO secretion were inhibited in the presence of the specific p-STAT3 inhibitor JSI-124. All the data indicated that apoptotic cells could turn DCs to inhibitory DCs, which might play important roles in the suppression of immune responses. STAT3 activation and the consequent release of NO are responsible for the inhibitory functions of DCapos.