Compartmentalized and systemic control of tissue immunity by commensals

Abstract

The body is composed of various tissue microenvironments with finely tuned local immunosurveillance systems, many of which are in close apposition with distinct commensal niches. Mammals have formed an evolutionary partnership with the microbiota that is critical for metabolism, tissue development and host defense. Despite our growing understanding of the impact of this host-microbe alliance on immunity in the gastrointestinal tract, the extent to which individual microenvironments are controlled by resident microbiota remains unclear. In this Perspective, we discuss how resident commensals outside the gastrointestinal tract can control unique physiological niches and the potential implications of the dialog between these commensals and the host for the establishment of immune homeostasis, protective responses and tissue pathology.

Figure 1

Tissue-specific modes of host-commensal interactions at distinct barrier sites. The gastrointestinal tract has the most abundant commensal niches in the body. A thick mucus layer separates the intestinal epithelium from resident microbes. Certain commensal species such as segmented filamentous bacteria (SFB) can penetrate the intestinal mucosal layer and reside in intimate contact with epithelial cells and in Peyer’s patches. By virtue of their localization, these species are uniquely poised to influence immune functions. Commensal microorganisms reside on the surface of the skin and appendages, such as hair follicles, sebaceous glands and sweat glands. These appendages may be critical sites of interactions between immune cells and commensals in the skin. The oral cavity contains several microenvironments that house commensal microbes including buccal mucosa, saliva, teeth and gingiva. Individual teeth house bacteria both above and below the gumline, that have been shown to modulate immunity in the surrounding gingiva; additionally, commensal bacteria constitutively form biofilm at this tissue site. In the respiratory tract, the composition of commensals is conserved across different geographical locations but the density of commensals is greatest in the upper airways and is less in the lower airways. The vaginal mucosa is dominantly colonized by Lactobacillus spp., but little is known about the precise localization of commensals in this niche and how fluctuations associated with sexual activity, menstrual cycle and pregnancy impact the microbiota in this site.

Figure 2

Localized and systemic regulation of the immune system by distinct commensal niches. (a) Commensal bacteria in the skin dynamically regulate the cutaneous effector and T_reg cells by amplifying inflammatory signals (IL-1). Similarly, commensal signals in the oral mucosa and respiratory tract promote the production of IL-1, and of IL-1 and IL-18, respectively. In the gastrointestinal tract, commensal ligands (TLR, NLR and Nod ligands) and commensal metabolites (short-chain fatty acids) instruct immunity locally. Trace amounts of commensal byproducts enter blood circulation and localize to the bone marrow where they control immune cell development and function. (b) Skin commensals control protective T_H1 responses during a dermal infection in an IL-1–dependent manner. A TLR2 ligand, lipoteichoic acid (LTA) specifically derived from S. epidermidis ameliorates exuberant production of TNF and IL-6 during skin inflammation. The signals involved in regulation of intestinal immunity during localized inflammatory responses are similar to those involved in controlling immune homeostasis, but these commensal derived signals are greatly amplified during an inflammatory response. Signals from gut microbiota may diffuse more readily into systemic circulation during gut inflammation. (c) Intestinal microbiota has been identified as a key modulator of systemic immunity. Gut-dwelling commensals can promote pathology in various mouse models of autoimmunity (experimental autoimmune encephalomyelitis (EAE), diabetes and arthritis). The intestinal microbiota also regulates viral immunity in the lung by controlling macrophage responses and inflammasome activation. Allergic airway inflammation is negatively regulated by signals from the flora that down-modulate responses of immune effectors, including production of IgE by plasma cells, development of basophils and accumulation of iNKT in the gut and lung. innate Natural Killer T cells (iNKT), experimental autoimmune encephalomyelitis (EAE), Rheumatoid arthritis (RA), polysaccharide A(PSA), polymorphonuclear neutrophils (PMN), Peptidoglycan (PGN), Antimicrobial peptides (AMPs).