Tissue-Resident Immune Cells in Humans

Abstract

Tissue-resident immune cells span both myeloid and lymphoid cell lineages, have been found in multiple human tissues, and play integral roles at all stages of the immune response, from maintaining homeostasis to responding to infectious challenges to resolution of inflammation to tissue repair. In humans, studying immune cells and responses in tissues is challenging, although recent advances in sampling and high-dimensional profiling have provided new insights into the ontogeny, maintenance, and functional role of tissue-resident immune cells. Each tissue contains a specific complement of resident immune cells. Moreover, resident immune cells for each lineage share core properties, along with tissue-specific adaptations. Here we propose a five-point checklist for defining resident immune cell types in humans and describe the currently known features of resident immune cells, their mechanisms of development, and their putative functional roles within various human organs. We also consider these aspects of resident immune cells in the context of future studies and therapeutics.

Keywords: adaptive immunity; human immune system; innate immunity; lymphoid organs; mucosal tissues.

Figure 1

Features of myeloid and lymphoid residency. (a) Blood monocytes express surface markers CD14, CD16, CCR2, and CX3CR1. In tissues, macrophages downregulate CD14 and CD16 and are capable of in situ self-renewal regardless of their ontogeny. Both embryo-derived and monocyte-derived macrophages express CD163, CD206, and CD68. Monocyte-derived macrophages uniquely express CCR2, CX3CR1, and to some extent CD11c, while embryo-derived macrophages express CD209, CD169, and MARCO. (b) Lymphoid cells in the blood express S1PR1; the T cells also express CX3CR1 and NK cells, CD16. They express transcription factors associated with quiescence, including KLF2, TCF1, and LEF1. In tissues, both lineages of lymphoid cells possess similar features of residency, including CD69, CD103, CXCR6, and CD49a, and exhibit low turnover rates that contribute to their maintenance. Tissue-resident memory T cells upregulate the transcription factors RUNX3 and Notch, along with cell surface markers PD-1 and CD101, while tissue-resident NK cells upregulate CD56 and various natural cytotoxicity receptors along with the transcription factors Eomes and Hobit. Abbreviations: NK, natural killer; TCR, T cell receptor.

Figure 2

Developmental pathways for resident immune cells. Myeloid and lymphoid progenitors are present in the bone marrow and differentiate into myeloid and lymphoid cells, respectively. Myeloid cells enter circulation as monocytes and travel along chemotactic CX3CL1/CX3CR1 and CCL2/CCR2 gradients to migrate into tissues and differentiate into macrophages. Embryo-derived macrophages migrate from the fetal liver and upregulate genes BMX, SPIC, and MMP1, allowing them to take up residence in specific tissues. Lymphoid progenitors either differentiate into NK cells and enter circulation due to IL-15 or migrate to the thymus to undergo maturation and selection. Two major types of T cells develop: γδ T cells exit the thymus and seed peripheral tissues via the circulation without need for prior sensitization, while naive αβ T cells migrate from the thymus to lymph nodes, where they recognize their cognate ligand presented by dendritic cells and subsequently proliferate into Teff cells. Teff cells differentiate into Tcm cells, Tem cells, or Temra cells. Teff cells, Tcm cells, and Tem cells can traffic between lymphatics and circulation, whereas Temra cells are restricted to the blood. Tem cells in circulation move into tissues, where local antigen, and expression of certain transcription factors, including Hobit and RUNX3, can promote Trm cell formation. Trm cells can also turn over in situ and clonally expand following activation, which may contribute to their maintenance. Additionally, Trm cells upregulate CD103 and CXCR6 in response to TGF-β and CXCL16, respectively. NK cells in blood migrate into tissues along chemotactic gradients (CCL3/CCR5 or CXCL16/CXCR6) and upregulate residency-associated molecules mediated by Eomes, Hobit, and TGF-β. Abbreviations: DC, dendritic cell; NK, natural killer; Tcm, central memory T; TCR, T cell receptor; Teff, T effector; Tem, effector memory T; Temra, terminally differentiated memory T; TF, transcription factor; Trm, tissue-resident memory T; trNK, tissue-resident NK. Figure adapted from images created with BioRender.com.

Figure 3

Interactions and functional roles of resident immune cells during homeostasis, inflammation, and tissue repair. (a) Resident immune cells during homeostasis: Expression of CD163, CD209, and MARCO on macrophages promotes homeostatic phagocytosis of benign particulates. Trm cells express PD-1, and NK cells express KIRs; these interact with PD-L1 and MHC-I molecules, respectively, to control inflammation. Additionally, NK cells, γδ T cells, and CD8⁺ Trm cells express NKG2D to survey tissue for damaged or infected cells. (b) Tissue inflammation: Macrophages initiate inflammation by secreting IL-1β, IL-6, IL-8, CXCL1, CCL2, CCL7, and G-CSF, which recruit activated monocytes, neutrophils, NK cells, and effector T cells to the tissues, as well as IL-15 and IL-18 to activate NK cells in situ. They also upregulate CD163, CD209, and MARCO to increase phagocytic capacity; CD80/86 to activate T cells; and MICA/B, which promote NK cell activation. Trm cells, γδ T cells, and NK cells secrete IFN-γ, TNF-α, IL-2, perforin, and GzmB. Activated CD4⁺ T cells also provide help to recruited B cells, resulting in pathogen-specific neutralizing antibody production. CD16 expression on NK cells and γδ T cells can induce antibody-dependent cellular cytotoxicity. (c) Immune resolution and tissue repair: Macrophages undergo efferocytosis and secrete IL-10 and growth factors to promote reepithelialization. Trm cells may inhibit proliferation through CD101 expression while both recruited Tregs and Trm cells can secrete IL-10 and express CTLA4 to prevent T cell activation. NK cells directly lyse effector T cells that upregulate MICA/B via perforin and GzmB secretion and also produce CCL1/3/4/5 to recruit Tregs. Finally, macrophages and T cells produce Areg and other growth factors, while NK cells secrete IL-22 to promote reepithelialization and tissue repair. Abbreviations: Areg, amphiregulin; G-CSF, granulocyte colony-stimulating factor; KIR, killer immunoglobulin–like receptor; NK, natural killer; TCR, T cell receptor; Tem, effector memory T; Treg, regulatory T cell; Trm, tissue-resident memory T. Figure adapted from images created with BioRender.com.