Mechanisms of T Cell Organotropism

Cell. Mol. Life Sci. DOI 10.1007/s00018-016-2211-4 Cellular and Molecular Life Sciences REVIEW Mechanisms of T cell organotropism 1 1 1 Hongmei Fu • Eleanor Jayne Ward • Federica M. Marelli-Berg Received: 25 February 2016 / Revised: 21 March 2016 / Accepted: 22 March 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Protective immunity relies upon T cell differ- APCs Antigen presenting cells entiation and subsequent migration to target tissues. BATF Basic leucine zipper transcription factor Similarly, immune homeostasis requires the localization of CLA Cutaneous lymphocyte-associated antigen regulatory T cells (Tregs) to the sites where immunity takes CNS Central nervous system place. While naı¨ve T lymphocytes recirculate predomi- CTLA-4 Cytotoxic T lymphocytes antigen 4 nantly in secondary lymphoid tissue, primed T cells and DCs Dendritic cells activated Tregs must traffic to the antigen rich non-lym- DETCs Dendritic epidermal T cells phoid tissue to exert effector and regulatory responses, EAE Experimental autoimmune encephalomyelitis respectively. Following priming in draining lymph nodes, ECs Endothelial cells T cells acquire the ‘homing receptors’ to facilitate their FoxP3 Forkhead Box P3 access to specific tissues and organs. An additional level of GALT Gut-associated lymphoid tissue topographic specificity is provided by T cells receptor GPR G protein-coupled receptor recognition of antigen displayed by the endothelium. Fur- GVHD Graft-versus-host disease thermore, co-stimulatory signals (such as those induced by HGF Hepatocyte growth factor CD28) have been shown not only to regulate T cell acti- HIV Human immunodeficiency virus vation and differentiation, but also to orchestrate the HSV Herpes simplex virus anatomy of the ensuing T cell response. We here review IELs Intraepithelial lymphocytes the molecular mechanisms supporting trafficking of both IPEX Immune polyendocrine enteropathy X-linked effector and regulatory T cells to specific antigen-rich syndrome tissues. KLF2 Kru¨ppel-like factor 2 LFA Lymphocyte function-associated antigen Keywords Homing receptors Á T lymphocytes Á LNs Lymph nodes T cell migration Á Organotropism LP Lamina propria MAdCAM-1 Mucosal addressin cell adhesion molecule-1 Abbreviations MHC Major histocompatibility complex ACD Allergic contact dermatitis MLCs Memory lymphocyte clusters Ang II Angiotensin II MLNs Mesenteric lymph nodes MMP Matrix metalloproteinases mTOR Mammalian target of rapamycin & Federica M. Marelli-Berg NOD Non-obese diabetic [email protected] PLNs Peripheral lymph nodes PI3K Phosphatidylinositol-30-kinase 1 William Harvey Research Institute, Heart Centre, Barts and PNAd Peripheral lymph node addressin the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London PSGL-1 P-selectin glycoprotein ligand-1 EC1M 6BQ, UK PPs Peyer’s patches 123 H. Fu et al. RA Retinoic acid eventually transmigrate into the tissue. Lymphocyte RAR Retinoic acid receptor transendothelial migration can occur at the junction RALDH Retinaldehyde dehydrogenase between apposing ECs (paracellular route) without dis- S1PR1 Sphingosine-1-phosphate receptor 1 rupting the endothelial monolayer in a complex process S1P Sphingosine-1 phosphate known as trans-endothelial migration (TEM) or diapedesis SDF-1 Stromal-derived factor-1 involving the junctional adhesion molecules [8]. Alterna- SLOs Secondary lymphoid organs tively, leukocytes can migrate across the EC body into the TEM Trans-endothelial migration tissue known as the transcellular route [9]. Once across the TGF-b Transforming growth factor beta endothelial barrier, migrating lymphocytes continue to TCM Central memory T cells move through the subendothelial matrix [8] and the TEFF Effector T cells extravascular tissue to the site of inflammation in response TEM Effector memory T cells to chemotactic gradients [3]. Further details on the TRM Tissue resident memory T cells extravasation process can be found in a recent review by Th T helper cells Nourshargh and colleagues [10]. Tregs Regulatory T cells A wide range of adhesion molecules and chemokines iTregs Induced Tregs expressed on the ECs are required to bind to their counter nTregs Naturally occurring Tregs receptors on the migrating lymphocytes, directing lym- VA Vitamin A phocyte entry into the tissue [11]. The endothelium of VCAM-1 Vascular cell adhesion molecule-1 different organs is characterized by preferential expression VLA Very late antigen (VLA) of combinations of these molecules, thus being endowed with the ability to selectively recruit distinct lymphocyte subsets. During priming, the local microenvironment and cellular interactions induce T lymphocytes to express a Introduction: lymphocyte recirculation unique set of adhesion molecules and chemokine receptors and homing (the ‘homing’ receptors) so that antigen-experienced T cells acquire the ability to interact with organ-specific ECs Effective immune surveillance relies on the continuous and migrate to distinct target tissues [12–15]. Given that trafficking of lymphocytes through blood, lymphoid organs recurrent infections are likely to affect the same organ, the and non-lymphoid tissue in a process known as recircula- acquisition of tissue tropism by memory T cells contributes tion [1]. The physiological process by which lymphocytes to the effectiveness of recall responses. We here review the leave circulation, cross endothelium, find and localize to molecular interactions and mechanisms which underlie the particular tissues is known as extravasation [2]. In healthy ability of distinct memory T cell populations to migrate to tissue, the vascular endothelium forms a non-thrombotic, different non-lymphoid sites where antigen is located. non-adhesive barrier, and is impermeable to macro- molecules [3]. Upon inflammation, endothelial cells (ECs) undergo physiological and molecular changes such as the up-regulation of adhesion molecule expression. This in turn Naı¨ve T cell homing to secondary lymphoid organs allows the exit of lymphocytes across the endothelium into (SLOs) the tissue without disrupting endothelial integrity. The initial stage of lymphocyte trafficking is mostly Naı¨ve and memory T cells display different surface mediated by selectins, which are responsible for lympho- molecules which define their functional properties and cyte transient tethering and rolling on the endothelium [4]. migratory patterns [16–19]. Naı¨ve T cells have little or no This initial contact between the circulating lymphocytes ability to produce cytokines [20]. They recirculate from the and the endothelium monolayer facilitates lymphocyte blood, through secondary lymphoid organs (SLOs), into the exposure to chemokines displayed on the EC surface, lymphatic vessels and back to the blood [14, 21]. SLOs which induces intracellular signalling responses leading to include peripheral lymph nodes (PLNs), spleen, gut-asso- lymphocyte integrin activation. Activated integrins bind to ciated lymphoid tissue (GALT) including Peyer’s patches their ligands, such as the intercellular adhesion molecule-1 (PPs), and bronchus-associated lymphoid tissue [22]. (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), Homing of naı¨ve T cells to the PLNs requires the and mucosal addressin cell adhesion molecule-1 (MAd- expression of CD62L and the chemokine receptor CCR7. CAM-1), expressed on the endothelium, resulting in the CD62L binds to peripheral lymph node addressin (PNAd) firm arrest of lymphocytes on the endothelium [5–7]. Fol- expressed on the high endothelial venules (HEVs) of PLNs lowing firm adhesion on the EC monolayer, lymphocytes and mesenteric lymph nodes (MLNs) [23], while the 123 Mechanisms of T cell organotropism chemokine receptor CCR7 binds to the chemokines CCL19 In humans, the majority of T cells entering the PPs are and CCL21 expressed by HEVs of the PLNs [24, 25]. found to be naı¨ve T cells. This process requires the inter- CCL21 is also expressed in PPs [26]. Naı¨ve T cells have action of integrin a4b7 on T cells and MAdCAM-1 on the also been shown to utilize CXCR4, which is the receptor mucosal vasculature [26, 34]. Consistent with this obser- for the chemokine stromal cell-derived factor 1 (SDF-1, vation, human naı¨ve T cells constitutively express low levels CXCL12), to circulate through SLOs [27]. It has been of a4b7 [35, 36]. Other studies subsequently showed that shown that mineralocorticoid receptor signalling con- both CD62L and a4b7 are required in a sequential and syn- tributes to human naı¨ve T cells migration to lymph nodes ergistic manner to mediate naı¨ve T cell migration to the (LNs) by increasing CD62L, CCR7, and CXCR4 expres- MLNs [37]. CD62L binds to the PNAd expressed on the sion. Sleep-dependent release of endogenous aldosterone MLNs, which induces the initial rolling and tethering of T activates mineralocorticoid receptors on naı¨ve T cells. This cells during transendothelial migration; a4b7 integrins sub- leads to an increase in the expression of CCR7 and CD62L, sequently bind to MAdCAM-1 and mediate firm adhesion as well as of CXCR4. Central memory T cells with lymph and transmigration. T cell migration to the PPs is reduced by node-homing capacity were also affected. This could 55 % in mice that are deficient for CD62L; and mice lacking explain the beneficial effect of sleep on mounting an b7 integrin expression have been found to display a 90 % adaptive immune response [28]. Naive T cells enter the reduction in lymphocyte migration to

Load more