Introduction

Mucosal Immunology Group

Overview of Research Area 

Key words: lymphocyte, migration, trafficking, chemokines, homing, mucosa, dendritic cells

Key Goals 

1. Understanding mechanisms regulating leukocyte recruitement to mucosal surfaces
2. Identifying the molecules regulating tissue tropic lymphocyte entry to non-lymphoid tissues
3. Determining the underlying mechanisms regulating the generation of tissue tropic lymphocyte subsets

Mucosal tissues such as the airways and intestine present an enormous surface area to the outside environment and are thus not surprisingly the primary site of entry for many pathogens including viruses and bacteria. Protection of these surfaces with components of the adaptive immune system is critical for maintaining the integrity of the mucosal barrier and well being of the host, and the efficient and organized entry of immune cells to mucosal sites represents an important part of this process. Key players within the adaptive immune system are subsets of immune cells, termed lymphocytes that display tropism for specific tissue effector sites (for example the skin and intestine). Despite their beneficial role in mucosal immune defense dysregulated lymphocyte accumulation within these sites may also occur and is thought in part to underlie the induction and maintenance of chronic mucosal inflammatory disease (for example Inflammatory Bowel Disease (IBD) such as Crohn’s disease and Ulcerative Colitis, as well as enteropathies associated with food hypersensitivity such as coeliac disease). Our group focuses on understanding the mechanism by which lymphocytes gain entry into mucosal tissues, the molecular signals that are involved in this process and how such tissue tropic lymphocytes are generated.

Overview of lymphocyte migration 

Circulating naïve lymphocytes enter secondary lymphoid organs across High endothelial venules (HEVs) but are largely excluded from non-lymphoid tissues. Following their activation in secondary lymphoid tissues, lymphocytes acquire specialized effector functions including the ability to secrete cytokines and induce cell lysis of target cells. A large fraction of these cells gain the ability to enter non lymphoid effector tissues such as the skin and mucosal tissues. Lymphocyte entry into secondary lymphoid organs and effector tissues is mediated by the consecutive interaction of cells adhesion molecules (CAMs) including selectins, chemokine/chemokine receptors, integrins and Ig superfamily members. Selective expression of CAMs on lymphocytes and vascular endothelial cells aid in directing specific subsets of lymphocytes to distinct anatomical locations.

Figure. 1. Multistep model of lymphocyte transmigration. (1) Lymphocytes in the blood initiate interaction with endothelial cells via sequential selectin-adressin interactions, mediating the characteristic lymphocyte rolling. (2-3) Upon binding their endothelial-displayed chemokine ligands, chemokine receptors signal to mediate integrin activation. (4) Following activation, integrins bind their Ig superfamily ligands on the endothelium, mediating firm adhesion, (5) and the lymphocyte can migrate across the endothelium.

 

Overview of the intestinal immune system 

The intestinal surface is comprised of a single layered epithelium that separates the contents of the lumen from the intestinal lamina propria (LP)

Figure 2. Schematic overview of the inductive and effector sites within the intestinal mucosa. DC, dendritic cell; FAE, follicle associated epithelium; IEL, FOLL, Follicle; intraepithelial lymphocyte; LPL, lamina propria lymphocyte; PP, peyers patch; MLN, mesenteric lymph node; SED, subepithelial dome. Arrows indicate the circulation route of GALT primed T cells

 
The inductive sites (secondary lymphoid tissues) of the intestine are Peyers Patches (PP) and mesenteric lymph nodes (MLN) whose afferent lymphatics drain the intestinal LP (Fig 1). Antigen enters PP via specialized microfold (M) cells within the Follicular Associated Epithelium (FAE) where it is taken up and processed by dendritic cells in the sub-epithelial dome (SED) for presentation to T cells. In contrast, luminal antigen accessing the intestinal LP is transported to MLN via draining lymphatics either directly or within mobilized DCs. Presentation of luminal antigen in the context of costimulation, to naïve T cells within PP or MLN, induces their activation and proliferation and a proportion of these cells re-enter the circulation via the thoracic duct and can localize to the two effector sites of the intestinal mucosa, the intestinal epithelium (as intraepithelial lymphocytes, IEL) and lamina propria (as lamina propria lymphocytes, LPL). Naive T lymphocytes are largely excluded from the intestinal mucosa, however, upon activation in gut associated lymphoid tissues (GALT (MLN, PP)) a proportion of naïve lymphocytes are converted into effector lymphocytes, whose altered phenotypic profile, including changes in chemokine receptor and cell adhesion molecule expression, allows them to migrate into this site. Two molecules expressed on GALT generated effector lymphocytes, and recognized as playing a central role in effector lymphocyte entry to the intestinal mucosa, are the integrin a4b7 whose ligand MadCAM-1 is expressed on intestinal microvacular endothelium and the chemokine receptor CCR9 whose ligand CCL25 is selectively expressed by small intestinal epithelial cells.

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