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. 2021 Sep 28;12:749708. doi: 10.3389/fimmu.2021.749708

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Copyright © 2021 Chiaranunt, Tai, Ngai and Mortha

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Intestinal MP heterogeneity is determined by distinct ontogeny, transcription profiles, and microanatomic locations. (A) Fetal liver monocytes and adult BM-derived monocytes seed the intestinal tract in two distinct waves, giving rise to at least three distinct MP populations in the gut: Tim-4^-CD4^- (DN) MPs, Tim-4^-CD4⁺ (SP) MPs, and Tim-4⁺CD4⁺ (DP) MPs. Monocytes require CCR2 and NR4A1 for the egress from the BM and differentiation into subsets. Monocytes have been suggested to differentiate into DN MPs in a RUNX3-dependent manner and in an environment rich in CSF1, whereas DP MPs require CSF1 and TGF-β. CSF2 plays a role in gut MP development and impacts the functional and developmental profile of MP, possibly through the actions of IRF5. However, the exact differentiation pathways and plasticity between DN, SP, and DP MPs are yet to be elucidated. The color separation (blue: fetal, light brown: adult) in (A) indicates the developmental origin of MPs. Dashed lines indicate potential developmental relationships among gut MPs. It remains unclear if DN, SP and DP MPs constituted a developmental continuum or follow three distinctly developmental pathways. Plasticity between each MP population also remains to be addressed. After birth, infiltration of adult BM-derived monocytes into the intestinal tract requires signals from the microbiome. (B) Post infiltration of the gut, MPs accumulate at distinct microanatomic locations across the intestinal tract. Close proximity with characteristic structures allows for the classification of intestinal MPs into vasculature-associated MPs (vMPs, red), epithelium-associated MPs (eMPs, light brown), nerve-associated MPs (nMPs, light blue) and lymphoid tissue-associated MPs (lMPs, violet). Despite their shared monocytic origin, there is evidence of preferential anatomic localization of MPs that has been factored into our current working model for intestinal MP development. (C) We propose a working model for gut MP development, in which precursors of distinct developmental origins (blue: fetal, light brown: adult) differentiate into DN, SP, and DP MPs. Colors indicate their accumulation at microanatomic locations like the vasculature (red), the epithelium (light brown), neurons (light blue) or lymphoid tissues (violet). Each MP identity depends on ontogeny, their microanatomic location, and the environmental signals therein. Dashed lines indicate plasticity or direct developmental relationships between DN, SP, and DP MPs.