Innate immune cellular therapeutics in transplantation

Abstract

Successful organ transplantation provides an opportunity to extend the lives of patients with end-stage organ failure. Selectively suppressing the donor-specific alloimmune response, however, remains challenging without the continuous use of non-specific immunosuppressive medications, which have multiple adverse effects including elevated risks of infection, chronic kidney injury, cardiovascular disease, and cancer. Efforts to promote allograft tolerance have focused on manipulating the adaptive immune response, but long-term allograft survival rates remain disappointing. In recent years, the innate immune system has become an attractive therapeutic target for the prevention and treatment of transplant organ rejection. Indeed, contemporary studies demonstrate that innate immune cells participate in both the initial alloimmune response and chronic allograft rejection and undergo non-permanent functional reprogramming in a phenomenon termed "trained immunity." Several types of innate immune cells are currently under investigation as potential therapeutics in transplantation, including myeloid-derived suppressor cells, dendritic cells, regulatory macrophages, natural killer cells, and innate lymphoid cells. In this review, we discuss the features and functions of these cell types, with a focus on their role in the alloimmune response. We examine their potential application as therapeutics to prevent or treat allograft rejection, as well as challenges in their clinical translation and future directions for investigation.

Keywords: MDSCs (myeloid-derived suppressor cells); cellular therapeutics; human monocyte-derived suppressor cells; innate lymphoid cells (ILCs); regulatory dendritic cells; regulatory macrophages; transplantation.

Figure 1

Immunosuppressive mechanisms of MDSCs. MDSCs express PD-L1, which activates Tregs and inhibits effector T cells by binding its cognate PD-1. In response to CSF/CSF1R signaling, MDSCs upregulate PD-L1. They express HO-1, which similarly inhibits effector T cells. MDSCs express iNOS which consumes L-arginine to produce NO, the latter of which then inhibits B cells, NK cells, and effector T cells. Finally, they produce TGF-β and IL-10 to activate Tregs and CCL-5 to recruit Tregs to the allograft.

Figure 2

Immunosuppressive mechanisms of regDCs. RegDCs express PD-L1 and FasL to inhibit or delete effector and memory T cells through direct cell-cell contact. They also inhibit effector T cell activation through HO-1 and IDO signaling. They activate and promote the differentiation of Bregs, Tregs, and double negative T cells, and secrete anti-inflammatory cytokines including TGFβ, NO, and IL-10. Finally, donor regDCs release exosomes carrying donor MHC, creating “cross-dressed” recipient DCs via trogocytosis. These recipient DCs then upregulate inhibitory cell surface receptors (such as PD-L1) and secrete anti-inflammatory cytokines (such as IL-10) to further inhibit alloreactive T cells.

Figure 3

Immunosuppressive mechanisms of Mregs. Mregs express IDO in response to IFN-γ signaling, which then inhibits effector T cell proliferation. They secrete TGF-β and IL-10 to activate and promote the expansion of Tregs. Additionally, Mregs promote the conversion of allogenic CD4⁺ T cells to inhibitory TIGIT⁺ Tregs through the TGF-β and IDO signaling pathways, among others. The TIGIT⁺ Tregs secrete IL-10 and arrest dendritic cell maturation, the latter of which promotes allogenic T cell anergy or deletion through the indirect allorecognition pathway.

Figure 4

Immunosuppressive mechanisms of ILC2s. ILC2s express ICOS and activate Tregs by binding their cognate ICOS-L. They secrete amphiregulin, which activates Tregs and M2 macrophages. ILC2s produce IL-4, IL-5, and IL-13, which then stimulate MDSCs, M2 macrophages, and Th2 helper T cells, promoting a Th2 polarized inflammatory response.