PMC

Lymphocytes involved in the intestinal immune response are organized in two compartments: inductive (A) and effector (B) sites. (A) Naïve lymphocytes (round cells) enter inductive sites through HEVs (polygonal) in PPs and MLNs, where they roll through L-selectin interactions with PNAd and become activated by surface-bound CCL19 and CCL21 that bind to CCR7. Lymphocyte α₄β₇ integrin interacts with MAdCAM-1 to mediate rolling and, after activation, firm adhesion. Once transmigrated into the parenchyma, lymphocytes encounter dendritic cells presenting antigen in the T cell zone of PP and MLN. RA produced by CD103 (α_E)⁺ dendritic cells induce or enhance expression of gut-trophic receptors α₄β₇ integrin and CCR9 chemokine receptor. Once activated in PP, the mucosal lymphoblasts then enter the gut-draining MLN. (B) When effector cells return back to the intestinal LP, CCR9⁺α₄β₇ ⁺ activated lymphocytes preferentially leave the circulation via MAdCAM-1 and CCL25 (small circles) expressing LP-associated post-capillary venuels. Some of these α₄β₇ ⁺CCR9⁺ LPLs are then destined to reside in the intestinal epithelium, attracted by CCL25. Switching from α₄β₇ ⁺ LPL to α_Eβ₇⁺ IEL occurs by the effect of TGF-β, locally secreted by intestinal epithelium (cuboidal). As a result, most IELs express only α_Eβ₇ integrin. The α_Eβ₇⁺ IEL cells reside between epithelial cells via interaction with E-cadherin and this interaction is likely promoted by CCR9/CCL25 signaling. Thick arrows indicate migration; thin arrows indicate secretion of soluble mediators.