Figure 2.

While phagocytosis of TLR ligand-carrying apoptotic cells instructs T_H17 differentiation, innate recognition of other forms of cell death may have different immune consequences. DC facing an infection sense a multitude of PAMPs expressed by microbes via a variety of PRRs such as TLR and NLRs. DC undergo a maturation program leading to the expression of T-cell co-stimulatory molecules and the secretion of inflammatory cytokines including IL-6, IL-12, IL-1β, and TNF-α. IL-12 production is the main driver of CD4⁺ T-cell differentiation into T_H1 [6]. By contrast, when DC phagocytose an apoptotic cell, they induce a non-inflammatory response associated with the differentiation of T_reg cells. Cells that succumb to apoptosis express ‘eat-me’ signals including exposure of PS at the outer leaflet of the plasma membrane. PS is subsequently recognized by DC through several receptors such as TIM-4, stabilin-2, BAI1, MER, and the α_vβ₃ integrin. While TIM-4, stabilin-2, and BAI1 recognize PS directly, MER or the α_vβ₃ integrin require interaction with bridging molecules such as GAS6 or MFG-E8, respectively, to recognize PS and initiate phagocytosis. DC can then prime CD4⁺ T cells to differentiate into regulatory T cells by secreting anti-inflammatory cytokines such as TGF-β and IL-10. In the particular case of an apoptotic cell carrying TLR ligands, for example a neutrophil undergoing apoptosis following phagocytosis of bacteria, the combination of pro-inflammatory signals from activated TLRs with signals driven by the apoptotic cell cargo induces a unique cocktail of cytokines including IL-6, TGF-β, and IL-23, and triggers T_H17 differentiation. Other types of cell death such as necrosis and pyroptosis also exist and these are thought to be immunogenic because of the release of cellular contents and inflammatory cytokines such as IL-1β that can activate DC [49]. While HMGB1 released by necrotic cells is known to result in DC maturation when recognized by RAGE, the ligand for CLEC9A, a C-type lectin receptor implicated in recognition of necrotic cells, remains to be discovered [49]. The consequence of phagocytosis of necrotic or pyroptotic cells on CD4⁺ T-cell differentiation is not known. HMGB1, high-mobility group box 1; RAGE, receptor for advanced glycation end-products; CLEC9A, C-type lectin domain family 9, member A.