The RUNX complex: reaching beyond haematopoiesis into immunity

Abstract

Among their diverse roles as transcriptional regulators during development and cell fate specification, the RUNX transcription factors are best known for the parts they play in haematopoiesis. RUNX proteins are expressed throughout all haematopoietic lineages, being necessary for the emergence of the first haematopoietic stem cells to their terminal differentiation. Although much progress has been made since their discoveries almost two decades ago, current appreciation of RUNX in haematopoiesis is largely grounded in their lineage-specifying roles. In contrast, the importance of RUNX to immunity has been mostly obscured for historic, technical and conceptual reasons. However, this paradigm is likely to shift over time, as a primary purpose of haematopoiesis is to resource the immune system. Furthermore, recent evidence suggests a role for RUNX in the innate immunity of non-haematopoietic cells. This review takes a haematopoiesis-centric approach to collate what is known of RUNX's contribution to the overall mammalian immune system and discuss their growing prominence in areas such as autoimmunity, inflammatory diseases and mucosal immunity.

Keywords: RUNX transcription factors; autoimmunity; haematopoiesis; immune system; mucosal immunity.

Figure 1

RUNX and T‐lymphocyte differentiation. In the thymic cortex, Runx1 is expressed in CD4⁻ CD8⁻ double‐negative (DN) thymocytes, reaching a maximum at DN3 before declining during DN3 to DN4 transition. Runx1 transcriptionally orchestrates interleukin 7 receptor α (IL‐7Rα) ‐mediated expansion, T cell receptor (TCR) γδ and TCR‐αβ rearrangement during these developmental stages. In addition, Runx1 is also a key factor for the differentiation of invariant natural killer T (iNKT) cells in the medulla cortex of the thymus. Following TCR‐mediated selection, Runx3 gains prominence and is a major driver of CD8⁺ T‐cell differentiation through the silencing of Cd4 and Thpok, master regulator of CD4⁺ differentiation. In the periphery, Runx3 promotes the maturation of CD8⁺ T cells into cytotoxic T lymphocytes (Tc/CTL) via its regulation of Eomes and key effector genes. In TCR‐activated CD4⁺ T cells, Runx3 cooperates with T‐bet to strengthen the T helper type 1 (Th1) phenotype by activating Ifng expression while suppressing Th2‐specific cytokine IL4. Runx proteins are also important in the differentiation and functions of regulatory T (Treg) cells through its regulation and interaction with Foxp3. Lastly, Runx proteins influence the development of Th17 in distinct ways. Runx could suppress or activate Rorγt depending on the presence of Foxp3, while interacting with RORγt to activate Il17 expression. Moreover, Runx1/3 are needed for the production of interferon‐γ (IFN‐γ) in a subset of Th17 cells important in the pathogenesis of autoinflammatory conditions. In this figure, key T lineage determinants that functionally interact with RUNX are labelled in blue and notable effector genes are labelled in brown. ETP denotes early thymocyte progenitors.

Figure 2

RUNX in B‐cell development and humoral immunity. In adult bone marrow, Runx1 is involved in the differentiation of B cells from common lymphoid progenitors (CLP). Specifically, Runx1 regulates and cooperates with Ebf for the transition of pre‐proB cells to pro‐B cells. Runx1 also takes part in the transition of large pre‐B cells to small pre‐B cells via V _H to DJ _H recombination as well as regulation of pre‐B cell receptor (BCR). Runx3 is necessary in the later stage of B‐cell development in secondary lymphoid tissues. Runx3 and Runx2 function downstream of transforming growth factor‐β (TGF‐β) ‐mediated IgA class switching, a key event in the development of B lymphoblasts. Runx1 is also needed to maintain high IgA expression on the surfaces of activated lymphoblasts. In human, RUNX1 further influences the differentiation of FCRL4⁺ memory B cells that normally reside in mucosal tissues.

Figure 3

The multifaceted contribution of RUNX in mucosal immunity. (1) Runx proteins are essential for the differentiation and effector functions of diverse cell lineages that participate in the mucosal immune system. These include T cells, B cells and dendritic cells (DC) for adaptive immunity; as well as macrophages, natural killer (NK) cells and epithelial cells for innate immunity. (2) Runx1 and Runx3 are critically involved in the specification of CD8⁺ cytotoxic T (Tc) and naive CD4⁺ helper T (Th) lymphocytes before their entrance into the periphery. Following antigen engagement and T cell receptor (TCR) activation, Runx1/3 coordinate the terminal differentiation of CD4⁺ T cells into Th1, Th2, Th17 and Treg cells, and CD8⁺ T cells into cytotoxic T lymphocyte (CTL) effector T‐cell lineages. (3) In B lymphocytes, Runx proteins play a crucial role in transforming growth factor‐β (TGF‐β) ‐mediated IgA class switching following antigen engagement. Runx proteins are also necessary for the maximal surface expression of IgA on activated B lymphoblasts and the maintenance of specialized memory B (Bmem) cells distributed at the mucosa. (4) The Runx complex is required for the formation of anlagen that initiate Peyer's patches and peripheral lymph node biogenesis. These secondary lymphoid tissues are home to naive peripheral lymphocytes and dendritic cells and are necessary for maintaining surveillance and homeostasis. (5) The mucosal epithelium is in direct contact with the microbial load and functions as a physical as well as an immune barrier. RUNX proteins are functionally important in a diverse range of mucosal epithelial cells, including those in the lung and gastrointestinal tract. RUNX3 is necessary for the homeostasis of an intact mucosal epithelium by regulating the proliferation and apoptosis of epithelial cells.1 RUNX proteins may further contribute to innate immunity within the epithelium by regulating cytokine production (such as IL23A) during infection and inflammation.129