Murine Myeloid Dendritic Cells That Phagocytose Apoptotic T Cells Inhibit the Immune Response via NO

Abstract

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.

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

“…In turn, DCs co-cultured with apoptotic cells up-regulate iNOS generation and STAT3 phosphorylation and can induce regulatory T cells after engulfing apoptotic cells. Importantly, DCs that phagocytose apoptotic T cells acquire inhibitory function toward CD4 + and CD8 + T cells [93]. These regDCs could not induce the generation of Tregs, but they were found to directly inhibit conventional DCs that initiate CD4 + and CD8 + T cell proliferation both in vitro and in vivo.…”

“…These regDCs could not induce the generation of Tregs, but they were found to directly inhibit conventional DCs that initiate CD4 + and CD8 + T cell proliferation both in vitro and in vivo. Soluble factors including NO play a role in the DC-induced suppression of CD4 + and CD8 + T cell proliferation [93].…”

CD8+ T activation attenuates CD4+ T proliferation through dendritic cells modification

“…The phenotypes and functions of these cells are highly plastic and modifiable by factors in the ambient environment [13,14]. Our and other's studies have shown that some special microenvironments can drive mature and immature DCs to differentiate into regulatory DCs, thereby suppressing their ability to induce CD4 + T responses [15][16][17][18]. Activated CD8 + T cells express many adhesion molecules on the cell membrane, and secret different cytokine profiles from its quiescent state.…”

“…Western blotting was done as previous reported [17]. In brief, protein was extracted from DCs by lysis buffer and boiled for 10 min.…”

State-of-the-art of regulatory dendritic cells in cancer

“…Besides IDO, regulatory DCs (in addition to macrophages) also produce arginase, which utilizes L-arginine (Norian, et al, 2009; Scarlett, et al, 2012), at least in mouse tumor models. Finally, as their immature myeloid precursors, regulatory DCs can also produce iNOS, responsible for inhibiting immune responses through nitric oxide production (Zhong, et al, 2012). …”