Figure 2

Multi-step homing mechanism for T_eff cell recruitment to the gut (small intestine). T_eff cells primed by Ag in Peyer’s patches and mesenteric LN draining gut (not shown) become imprinted with gut-homing molecules, among which include chemokine receptors CCR9 and CXCR4 and integrin α₄β_7.^{16, 17, 18} (Step 1) Circulating T_eff cells in postcapillary venules of the gut (small intestine) engage CCR9-CCL25 and CXCR4-CXCL12 thereby eliciting Gα_i-dependent signaling, activation of α₄β₇, and subsequent tethering and rolling on intestinal endothelial MAdCAM-1 (arrows; solid=known signaling, dotted=speculated signaling).^{16, 17, 18, 19, 20, 21, 22} CCL25 and CXCL12 are produced constitutively by epithelial cells (enterocytes) of the small intestine while MAdCAM-1 is expressed constitutively in HEV of gut Peyer’s patches and mesenteric lymph nodes (not shown) and by intestinal endothelium of the lamina propria.^{16, 17, 18, 19, 21} (Steps 2–3) Rolling of α₄β₇ on MAdCAM-1 eventuates in T_eff cell firm adhesion. (Step 4) T_eff cells undergo transendothelial migration into the lamina propria, facilitated by concentration gradients of immobilized CCL25 and CXCL12 on apical and basal endothelial GAGs, on epithelial GAGs, and within the lamina propria.^{16, 17, 18, 23} Accessory support of steps 2-4 may involve CXCR3-CXCL10 signaling (boxed).¹⁶ A subset of T_eff cells traverse the lamina propria and then embed themselves as intraepithelial lymphocytes (IEL) into the epithelial cell layer of the intestinal lumen.^{16, 17} This latter process is accompanied by concurrently decreased α₄β₇ and increased α_Eβ₇ expression, CCL25-CCR9 signaling and activation of α_Eβ₇ (arrow), and α_Eβ₇ binding to E-cadherin.^{16, 18, 24} During inflammatory reactions, the gut-homing repertoire is expanded to cause increased T_eff cell recruitment. This involves elevation in the expression of E/P-selectins, MAdCAM-1, VCAM-1, and ICAM on intestinal endothelium, along with CCR6-CCL20 signaling to increase T_eff cell adhesive interactions through selectin ligands, VLA-4, and LFA-1 (not shown).^{22, 25, 26, 27, 28}