Bone-Marrow-Resident NK Cells Prime Monocytes for Regulatory Function during Infection

Abstract

SUMMARY Tissue-infiltrating Ly6Chi monocytes play diverse roles in immunity, ranging from pathogen killing to immune regulation. How and where this diversity of function is imposed remains poorly understood. Here we show that during acute gastrointestinal infection, priming of monocytes for regulatory function preceded systemic inflammation and was initiated prior to bone marrow egress. Notably, natural killer (NK) cell-derived IFN-γ promoted a regulatory program in monocyte progenitors during development. Early bone marrow NK cell activation was controlled by systemic interleukin-12 (IL-12) produced by Batf3-dependent dendritic cells (DC) in the mucosal-associated lymphoid tissue (MALT). This work challenges the paradigm that monocyte function is dominantly imposed by local signals following tissue recruitment, and instead proposes a sequential model of differentiation in which monocytes are pre-emptively educated during development in the bone marrow to promote their tissue-specific function.

G2A Signaling Dampens Colitic Inflammation via Production of IFN-γ

“…Fig. 2A), an effect consistent with actions of IFNγ in other contexts (33, 43). We were unable to replicate enhanced intracellular staining of IL-10 in the resulting Ly6C int MHCII + monocytes in either WT or G2A −/− mice (data not shown), and levels of IL-10, known to be produced by other sources in colitis (44–46), were not different between G2A −/− and WT colitic mice.…”

“…IFNγ has, for example, been shown to mediate anti-inflammatory properties through induction of indoleamine 2,3-dioxygenase 1 (53), regulation of the methylation response (54) and induction of epithelial IL-10 receptors (20) supportive of healing responses by the epithelium. We also note that anti-inflammatory activities of IFNγ on monocytes have also recently been described in the context of gastrointestinal infection (43). …”

Harnessing the beneficial heterologous effects of vaccination

“…For instance, haematopoietic stem and progenitor cells exposed to Toll-like receptor 2 (TLR2) agonists generate macrophages that produce lower amounts of inflammatory cytokines and reactive oxygen species 71 . Moreover, NK cells prime monocytes for regulatory function in the bone marrow in response to T. gondii infection, an effect that is mediated at least in part by IFNγ programming of monocyte progenitors 72 . Epigenetic imprinting of haematopoietic progenitors may enable chronic persistence of training/tolerance effects.…”

Human Lymphoid Tissues Harbor a Distinct CD69+CXCR6+ NK Cell Population

“…A s effector lymphocytes of the innate immune system, NK cells contribute to the first line of immune defense through the lysis of virus-infected and malignant cells. Furthermore, NK cells play an important role in the initiation, enhancement, and regulation of immune responses, directly through the secretion of cytokines and chemokines, as well as via their interaction with other innate immune cells (1)(2)(3)(4)(5)(6)(7)(8).…”

“…However, the majority of NK cells are localized in lymphoid tissues (17). Data obtained from murine experiments indicate that lymphoid tissues are the primary site for cellular interactions between NK cells and other immune cells (4)(5)(6). In humans, CD56 bright NK cells are enriched in marrow and spleen and make up the vast majority of mature NK cells in lymph node (18)(19)(20)(21)(22).…”