Leukocyte Homing To The Gastrointestinal System

Associated with the gut are several unique lymphoid tissues including inductive sites (Peyer's patches and mesenteric lymph nodes) where lymphocytes undergo activation and effector sites (lamina propria of the intestinal villi) where lymphocytes carry out effector functions [135], Peyer's patches are formed by aggregates of lymphoid follicles covered with M cells and are scattered throughout the small intestine. M cells trap, concentrate, and present antigens to lymphocytes in the adjoining B and T cell follicles. Naïve lymphocytes enter the Peyer's patches through high endothelial venules (HEV) where they undergo activation and differentiation to enteric antigens. These activated lymphocytes then traffic to mesenteric lymph nodes to undergo final maturation. Finally, activated lymphocytes enter the effector sites in the intestinal epithelial tissue and reside either between the epithelial cells or below epithelial cells in the core of the intestinal villi (lamina propria). These effector or memory cells either settle within the epithelium or lamina propria or emigrate via local collecting mesenteric lymph nodes before returning to the circulation. The lymphocytes found within the epithelium, called intraepithelial lymphocytes, are almost exclusively CD8+T cells, whereas lymphocytes in the lamina propria are predominantly IgA-antibody secreting B cells and CD4+CD45RO+ memory T cells [136], These latter memory T cells display a much lower proliferative response to antigens than do circulating cells [136,137], This is an evolutionary adaptation to the higher concentration of antigen within the mucosal environment. By requiring a higher activation threshold for T cells, potentially unnecessary and detrimental responses are avoided.

The intraepithelial cells on the other hand are mostly CD8oca+ and have a TCRyô phenotype in comparison to the TCRap phenotype of the memory T cells [138]. These CD8aa+TCRy§ T cells are thought to develop locally from cryptopatch precursor cells [138]. The intraepithelial lymphocyte compartment of the gut is highly enriched in yô T cells, yet their role in gastrointestinal immunity is not fully understood [139]. yô T cells are unique in that they are capable of different effector functions, including inflammatory cytokine production, cytolytic potential, as well as repair of epithelial tissue [139].

Chemokine mediated lymphocyte trafficking to Peyer's patches is similar to that of ordinary lymph nodes. CCR7, in conjunction with CXCR4, guides T cells and naïve B lymphocytes to Peyer's patches [134]. T cells lacking CCR7 show a defect in entering Peyer's patches [125]. Furthermore, T cells preferentially arrest in areas of the HEV where CCL21/SLC expression is high [140], Expression of CCL19/ELC/MIP-3|3 has also been reported in Peyer's patches [141], As expected, T and B cells show selectivity as to which areas of the Peyer's patches vasculature they adhere. T cells have been shown to accumulate in the interfollicular HEV, while B cells accumulate in or near HEV follicles. This ensures appropriate segregation of B and T lymphocytes into the correct lymphoid compartments [140], This difference is likely due to CXCR5 expression on B lymphocytes, since its ligand, CXCL13/BLC/BCA-1, is found selectively in Peyer's patches follicular HEV [134], Together, this demonstrates that CCR7, CXCR4, and CXCR5 play an important role in trafficking of T and B cells into Peyer's patches.

Chemokine receptors are also important in directing migration of cells into the lamina propria. CCR9 is expressed on CD4+ and CD8+ memory T cells bearing the integrin aJ37 in the lamina propria and within the intestinal epithelium of normal individuals [142], Lymphocytes from all other normal and inflamed tissues have been shown to be CCR9" [143], Indeed, CCL25/TECK, the ligand for CCR9, induces chemotactic function within lymphocytes from the small intestine, but not the colon. Coupled with the observation that mesenteric lymph nodes that drain the small intestine contain a higher percentage of CCR9+ lymphocytes than do mesenteric lymph nodes draining the colon [144], This suggests that CCR9 expression is uniquely induced in naïve T lymphocytes within the mucosal environment of the small intestine. Consistent with this hypothesis, CCL25/TECK is expressed in the small intestine by endothelial cells, epithelial cells, and a small subset of intestinal crypt cells within the lamina propria, but is not expressed in the colon, skin, lung or salivary glands [143,144], Most recently, it was shown that CD8+ cells activated in mesenteric lymph nodes maintained functional expression of CCR9, whereas CCR9 was rapidly downregulated on CD8+ cells activated in the peripheral lymph nodes [145], Furthermore, Sven-sson et al. [145] demonstrated that these CCR9+CD8+ cells preferentially migrate to the small intestinal mucosa and that in vivo neutralization of CCL25/TECK impaired the migration of these cells to small intestinal epithelium. Unfortunately, the mechanism of yô T cell recruitment to the intraepithelial lymphocyte compartment is still poorly understood. CCR9 deficient animals have been shown to have a significant decrease of intraepithelial TCRyô+CD8+ T cells in the in the gut, although the number of TCRa(3+CD8+ or TCRap CD4' T cells remained unaltered [146], This suggests that CCR9 mediates recruitment of y8 T cells into the gut.

While CCR9 expression in the gut primarily consists of CD3+ T cells, B cells and natural killer cells also express the receptor [144], This expression on B cells is clearly relevant since Bowman et al. [147] recently reported that CCL25/TECK is a potent chemoattractant for IgA-antibody secreting cells, recruiting them from the spleen, Peyer's patches and mesenteric lymph nodes. Therefore, it is evident that CCL25/TECK and CCR9 play a critical role in homing of effector T and B lymphocytes to the small intestine.

In addition to the involvement of CCR9 in small intestinal homing a number of other chem-okine receptors, which are widely known to play an important role in other tissues, are also expressed on T cells in the gastrointestinal system. For example, CXCR3, CCR5, and CCR2 chemokine receptors are expressed on lamina propria T lymphocytes, intraepithelial T lymphocytes, and CD45RO+p7M gut homing memory T cells [148], CXCR3 has been shown to be a functional receptor on intraepithelial and lamina propria lymphocytes [ 148] and the expression of its ligand CXCL10/IP-10 has been reported in normal colon lamina propria [149], Similarly, CCR5 has also been shown to be functional on intraepithelial and lamina propria lymphocytes and the expression of its ligand CCL5/RANTES has been reported in normal small intestine and colon epithelium and lamina propria [150], Lastly, the CCR6 ligand CCL20/LARC is expressed in the small intestine and colon by epithelial cells, especially those lining the Peyer's patches and may attract lymphocytes and dendritic cells to the intestinal epithelium [151]. These data suggest that CXCR3, CCR5 and CCR2 also play a role in preferential homing of T lymphocytes to normal mucosa.

Moreover, dendritic cells also play a crucial role in the immune network by processing antigen and activating lymphocytes. Particularly, CCR6 mediates recruitment of immature dendritic cells to the sub-epithelial dome of Peyer's patches [152]. Furthermore, CCR6 has been found to be expressed in myeloid CD1 lb+dendritic cells found exclusively in the sub-epithelial dome region of Payer's patches, where its ligand MIP-3a is expressed [153]. Therefore, CCR6 and MIP-3a mediate recruitment of dendritic cells precursors to the gastrointestinal tract under noninflammatory conditions.

While specific regulation of chemokines and their receptors is critical to directed cellular movement to and from Peyer's patches and lamina propria, differential expression of adhesion molecules is also of substantial importance. Peyer's patches uniquely expressed a modified mucosal addressin cell adhesion molecule, MadCAM-1, that adheres to CD62L/L-selectin preferentially expressed on naive T and B lymphocytes. Unmodified MadCAM-1 is expressed on endothelial cells within the lamina propria and adheres to the a4p7 integrins that are upregulated in activated gut-homing lymphocytes [154], Kunkel et al. [155] show that although the leukocyte rolling flux was suppressed in CD62L/L-selectin knockouts, Payer's patches were of normal size and cellularity. In P7 knockouts the rolling flux was normal, however the number of adherent leukocytes in HEV were greatly reduced [155],

It is clear that a variety of chemokines and chemokine receptors in conjunction with adhesion molecules are critical to immune homeostasis in the gastrointestinal system. CCR7, CXCR4 and CXCR5 mediate the homing of naive T and B lymphocytes to the inductive Peyer's patches. Subsequently, CCR5, CXCR3, CCR9 and CCR6 play a major role in trafficking of effector CD4+ and CD8+ T cells, dendritic cells as well as IgA-antibody secreting cells to the lamina propria and epithelial cell effector sites in the intestines. These effector cells play a crucial role in immune surveillance at antigen-rich mucosal sites that are routinely exposed to potential pathogens.

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