REVIEW ARTICLE published: 27 August 2013 doi: 10.3389/fimmu.2013.00254 Tissue specific heterogeneity in effector immune cell response SabaTufail 1 , Khan Farheen Badrealam 1 , Asif Sherwani 1 , Umesh D. Gupta 2 and Mohammad Owais 1 * 1 Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India 2 National JALMA Institute for Leprosy and OMD, Agra, India Edited by: Susan Swain, University of Massachusetts Medical School, USA Reviewed by: Phillip Scott, University of Pennsylvania, USA Shahram Salek-Ardakani, University of Florida, USA *Correspondence: Mohammad Owais, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, Uttar Pradesh 202002, India e-mail: owais_lakhnawi@yahoo.com Post pathogen invasion, migration of effectorT-cell subsets to specific tissue locations is of prime importance for generation of robust immune response. EffectorT cells are imprinted with distinct “homing codes” (adhesion molecules and chemokine receptors) during acti- vation which regulate their targeted trafficking to specific tissues. Internal cues in the lymph node microenvironment along with external stimuli from food (vitamin A) and sunlight (vit- amin D 3 ) prime dendritic cells, imprinting them to play centre stage in the induction of tissue tropism in effector T cells. B cells as well, in a manner similar to effector T cells, exhibit tissue-tropic migration. In this review, we have focused on the factors regulating the generation and migration of effector T cells to various tissues along with giving an overview of tissue tropism in B cells. Keywords: heterogeneity, effectorT cell, homing, dendritic cells, chemokine receptors INTRODUCTION Recent studies have revealed a diverse population of CD4 and CD8 T-cell effector subsets with distinct attributes in terms of pheno- type, function, cytokine polarization, and anatomical distribution (1, 2). Homing of T-cell subsets to specific tissue sites is crucial for evoking a robust immune response combined with immunologi- cal memory (3). Activation of naive T cells in secondary lymphoid organs (SLOs) results in their differentiation to a heterogenous pool of effector T cells equipped to perform diverse functions (4). The heterogeneity of the effector T cells so generated partially owes to the site where progenitor naive T cells were initially activated (3). To this end, T cells activated in the lymph node of a particular organ or tissue acquire the “homing codes” and become destined to migrate accordingly in order to perform effector functions. It has been well documented that T cells primed in skin-draining lymph nodes display skin homing receptors whereas the intestinal lymph node provides the specific environment to the activating T cells to express mucosal homing receptors (Figure 1). Such decisive role in lymphocyte recirculation is tightly regulated by expression of particular adhesion molecules and receptors on lymphocytes, combined with the spatial and temporal expression of ligands for these receptors by a variety of tissue cells. The kind of tissue spe- cific receptor-repertoire induced on the effector T cells is governed by the cues present in the lymph node microenvironment and external environment stimuli derived from food (vitamin A) and sunlight (vitamin D 3 ) which themselves are influenced by tissue derived dendritic cells (DCs). In the present review, some fun- damental concepts regulating the tissue specific heterogeneity in effector T cells has been discussed; emphasizing on cells, molecu- lar mediators, and environmental signals that are responsible for imprinting specialized trafficking programs. Since tissue-tropic B-cell subsets have also been recognized, we have outlined briefly the mechanisms inducing tissue specific heterogeneity in B cells as well. FACTORS INFLUENCING TISSUE TROPISM IN EFFECTOR T CELLS MOLECULAR INTERACTIONS Studies dating back to 1970s had unveiled that adoptively trans- ferred lymphocytes had a migratory pre-dilection for the tissues from which they were originally isolated (3, 5, 6). Lymphocytes isolated from mesenteric lymph nodes or Peyer’s patches (gut- associated lymphoid tissues) were found to populate preferentially mucosal effector sites (7–10). Later, “homing subsets” of T cells with distinct tissue tropism had been identified (11, 12). The selective expression of cellular adhesion receptors on T cells and vascular endothelium was found to be of prime importance in guiding T-cell subsets into and through distinct tissue compart- ments (13, 14). Since skin and intestinal tissues are the portal sites for pathogens entry, effector T cells infiltrate them enormously and this instigated the investigation of tissue-tropic homing of T cells at these sites. It has been evidenced that the α 4 β 7 -integrin and chemokine receptor CCR9 on T-cell surface target them to the lamina propria of the small intestine (3, 13–16). By contrast, skin homing T cells are characterized by expression of Endothelial cell selectin (E-selectin) and Platelet selectin (P-selectin) ligands in combination with CCR4 and/or CCR10 (3, 13–15, 17). The homing receptors for intestinal tissues, α 4 β 7 -integrin and CCR9, interact with MADCAM-1 (mucosal vascular addressin cell-adhesion molecule 1) and CCL25 (CC-chemokine ligand 25 also called TECK) respectively expressed on endothelial cells of gut lamina propria venules (17, 18). α 4 β 7 -Integrin or MADCAM-1 blocking by antibodies and gene knock-out studies have indi- cated their role in trafficking CD4 and CD8 effector T cells to intestinal tissues (3, 15, 18–21). It has been found that the propen- sity of T cells to colonize intestinal mucosa is abrogated if the β 7 -integrin chain expression is hampered. Moreover, antibod- ies blocking either α 4 β 7 -integrin or MADCAM-1 could ablate inflammation in animal models of colitis and human subjects www.frontiersin.org August 2013 |Volume 4 | Article 254 | 1