The gut microbiota and mucosal T cells

Review Article published: 26 May 2011 doi: 10.3389/fmicb.2011.00111 The gut microbiota and mucosal T cells Patrick M. Smith1,2 and Wendy S. Garrett 1,2,3,4,5* Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA 3 Department of Medicine, Harvard Medical School, Boston, MA, USA 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 5 The Broad Institute of MIT and Harvard, Cambridge, MA, USA 1 2 Edited by: Peter J. Turnbaugh, Harvard University, USA Reviewed by: Dennis L. Kasper, Harvard Medical School, USA Daniel Peterson, University of Nebraska-Lincoln, USA *Correspondence: Wendy S. Garrett, Department of Immunology and Infectious Diseases, Harvard School of Public Health, 665 Huntington Avenue, SPH 1, 9th Floor, Boston, MA 02115, USA. e-mail: It is intuitive that immune cells in the gut may require microbiota-derived cues for their differentiation. The proximity between host and microbe in the intestine would seemingly necessitate co-adaptation. However, it has been challenging to determine the members and features of the gut microbiota that influence immune system development and function. The recent identification of immunomodulatory members of the commensal microbiota is providing insight into the dependence of select, intestinal immune cell subsets on specific microbial species. In this review, we focus on the gut microbiota’s influence on the development and function of mucosal T cells subsets, specifically intraepithelial lymphocytes and lamina propria CD4 T cells. Keywords: gut microbiota, T cells, mucosal immunity Overview The mucosal immune system of the intestinal tract faces the challenge of co-existing with a diverse and dynamic community of microbes while remaining poised to protect and defend against invasive pathogens. This microbiota is an active participant in host metabolism and also provides critical developmental cues for the immune system. Studies from animals models lacking all microbes, referred to as germ-free, have established that gut microbes are crucial for the development, maturation, and function of the intestinal immune system and many aspects of systemic immunity. Mucosal T cells that reside within the epithelial cell layer and the lamina propria (LP) of the intestine are especially reliant on direct and indirect microbial signals for their proper differentiation and function. Recently a few species, Bacteroides fragilis, Candidatus Arthromitus sp. segmented filamentous bacteria (SFB), and Clostridium spp. from Clostridium Clusters III, IV, and XIVa have been identified that drive both effector and/or regulatory mucosal T cell maturation. In this review, we provide an introduction to mucosal T cell subsets, specifically intraepithelial lymphocytes and LP CD4 T cells, with a focus on the gut microbiota’s influence on their development and function. Intraepithelial T lymphocytes Below the tight junctions that join the plasma membranes of epithelial cells and residing above the basement membrane, are specialized subsets of gut T cells aptly named intraepithelial cell lymphocytes (IELs; Figure 1). IELs promote barrier repair, rapidly accumulate at sites of injury and infection, and defend against intestinal pathogens, such as Eimeria vermiformis (Roberts et al., 1996) and Salmonella spp. (Dalton et al., 2006). The majority of IELs express the CD8 glycoprotein, that binds MHC class I molecules (van Wijk and Cheroutre, 2009). IELs are categorized by the two chains that compose their T cell receptor: either alpha beta (αβ) or gamma www.frontiersin.org delta (γδ) heterodimers. αβ IELs are primarily derived in the thymus and migrate into the intestine after development (Sheridan and Lefrancois, 2010). In contrast, γδ T cells are derived extrathymically and while they constitute a small fraction of T cells in peripheral lymph nodes and the spleen, 50% of IELs in mice express γδ. In humans, 15% of IELs in the small intestine (SI) and upward of 40% in the colon are γδ positive (Kagnoff, 1998). In response to bacteria or intestinal injury, γδ IELs produce proinflammatory cytokines and chemokines that recruit neutrophils, eosinophils, and T cells. γδ IELs also promote epithelial healing via production of keratinocyte growth factor, which stimulates epithelial cell proliferation and restoration of barrier function (Yang et al., 2004). Despite the important role of γδ IELs in the intestine and their close proximity to luminal and mucosal microbes, relatively little was known about their regulation by the gut microbiota until recently. Because of their small absolute numbers and propensity for apoptosis when cultured ex vivo, γδ IELs have proven a challenging cell subset to study. The application of laser capture microdissection to the study of γδ IELs by the Hooper laboratory has provided a major advance for investigating this cell subset (Ismail et al., 2009). While germ-free (GF) mice have equal numbers of γδ IELs compared with conventionally raised mice (Bandeira et al., 1990), data have emerged on the significant role of the gut microbiota on γδ IEL function. Ismail et al. (2009) have begun to unravel an elaborate and dynamic cross-talk between commensal bacteria and γδ IELs during mucosal injury that both promotes wound healing and prevents invasion by opportunistic pathogens. By comparing the transcriptional profiles of colonic γδ IELs isolated from conventional and GF mice both prior to and following injury with the mucosal disruptant, dextran sulfate sodium (DSS), Ismail et al. (2009) identified key effectors in the γδ IEL microbiota-dependent response to injury. While upregulation of lysozyme was a microbiota-independent function of IELs, the May 2011 | Volume 2 | Article 111 | 1 Smith and Garrett The gut microbiota and mucosal T cells Beneath the epithelial cell layer’s basement membrane is the LP region of the mucosa. The LP of the small and large intestine is home to 70–80% of the body’s immune cells (Furness et al., 1999). As opposed to the intraepithelial lymphoid compartment, populated with CD8 T cells, the LP is dominated by T cells expressing the CD4 glycoprotein, which binds MHC class II. While there are CD8 αβ and γδ LP populations, we focus on the many helper and regulatory CD4 T cells that reside in the LP and the evolving understanding of their relationship with gut microbiota. Helper CD4 T cells (Th) represent a diverse collection of subsets with specific cytokines and chemokine profiles that result in activation and growth of cytotoxic T cells, promotion of myeloid cell bacte- ricidal activity, and B cell differentiation and antibody production. In general, T helper type 1 produce interferon-γ, TNF-α, and IL-12 and participate in host defense against intracellular pathogens; T helper type 2 produce IL-10, IL-13, IL-5, and IL-4 and defend against helm (...truncated)