The emerging family of RORγt+ antigen-presenting cells

Abstract

Antigen-presenting cells (APCs) are master regulators of the immune response by directly interacting with T cells to orchestrate distinct functional outcomes. Several types of professional APC exist, including conventional dendritic cells, B cells and macrophages, and numerous other cell types have non-classical roles in antigen presentation, such as thymic epithelial cells, endothelial cells and granulocytes. Accumulating evidence indicates the presence of a new family of APCs marked by the lineage-specifying transcription factor retinoic acid receptor-related orphan receptor-γt (RORγt) and demonstrates that these APCs have key roles in shaping immunity, inflammation and tolerance, particularly in the context of host-microorganism interactions. These RORγt⁺ APCs include subsets of group 3 innate lymphoid cells, extrathymic autoimmune regulator-expressing cells and, potentially, other emerging populations. Here, we summarize the major findings that led to the discovery of these RORγt⁺ APCs and their associated functions. We discuss discordance in recent reports and identify gaps in our knowledge in this burgeoning field, which has tremendous potential to advance our understanding of fundamental immune concepts.

Figure 1 |. A timeline of research leading to the characterization of RORγt⁺ APCs.

AIRE, autoimmune regulator; APC, antigen-presenting cell; APS1, autoimmune polyendocrine syndrome type 1; CRC, colorectal cancer; DC, dendritic cell; eTAC, extrathymic AIRE-expressing cell; ILC3, group 3 innate lymphoid cell; LTi cell, lymphoid tissue inducer cell; MHC-II, MHC class II; RORγt, retinoic acid receptor-related orphan receptor-γt; scRNA-seq, single-cell RNA-sequencing; T_H17 cell; T helper 17 cell; T_reg cell, regulatory T cell.

Figure 2 |. The phenotype and function of RORγt⁺ APCs in mice.

Retinoic acid receptor-related orphan receptor-γt (RORγt)⁺ antigen-presenting cells (APCs) are a heterogeneous family of cells, composed of many different subsets that differ in their ontogeny, tissue residence, functions and molecular characteristics. Three major subsets are highlighted. a, RORγt⁺ group 3 innate lymphoid cells (ILC3s). This group includes lymphoid tissue inducer (LTi)-like ILC3s, the first type of RORγt⁺ APC to be discovered, which are defined by the surface markers IL-7 receptor (IL-7R; also known as CD127) and the chemokine receptors CXCR6 and CCR6, by the transcription factor ZBTB46 (as well as RORγt), and by the T cell-impacting molecules MHC class II (MHC-II) and CD25. They lack expression of conventional co-stimulatory molecules such as CD40, CD80 and CD86. LTi-like ILC3s are tissue resident, found in lymph nodes and intestinal lamina propria during early life and adulthood. They co-localize with T cells in the follicular zone of mesenteric lymph nodes to restrain effector T cell responses or instruct the differentiation of regulatory T (T_reg) cells specific for intestinal microorganisms through various mechanisms. A separate subset of inflammatory ILC3s is derived from the circulation and can take residence in the central nervous system (CNS), where these cells have a proinflammatory role. Inflammatory ILC3s express the key surface markers IL-7R, CXCR6 and CCR6, the transcription factor T-bet, and the T cell-impacting molecules MHC-II, CD80 and CD86. Inflammatory ILC3s re-stimulate effector T cells that drive autoimmune neuroinflammation. b, RORγt⁺ extrathymic AIRE-expressing cells (eTACs). These cells — which include Janus cells, AIRE⁺ ILC3-like cells, and group I and III Thetis cells (TC I and TC III) — reside in secondary lymphoid organs and are defined by varying expression levels of Aire transcript and/or protein. They are CCR6⁺CXCR6^–, express no or limited IL-7R, express the transcription factor ZBTB46, and are positive for expression of MHC-II. A large fraction of these cells expresses high levels of co-stimulatory molecules such as CD80, CD86 and CD40. RORγt⁺ eTACs were shown to promote Candida albicans-specific T helper 17 (T_H17) cell responses. c, Rorc⁺ dendritic cell (DC)-like cells. These are a potential subset of RORγt⁺ APCs, including TC IV cells and potentially a minor fraction of cDC2Bs, that are found in early life lymph nodes. They express CD11c, CD11b, ZBTB46, MHC-II, CD80, CD86 and CD40, but no IL-7R, CXCR6 or AIRE, and are proposed to drive tolerogenic responses. EAE, experimental autoimmune encephalomyelitis; T_FH cell, T follicular helper cell; T_H2 cell, T helper 2 cell.