Effector and Regulatory T Cell Trafficking in Corneal Allograft Rejection

Figure 1

Overview of T cell trafficking in corneal allograft rejection. (I) Circulating naïve T (Th0) cells and regulatory T cells (Tregs) migrate to the parenchyma of draining lymph nodes via specialized postcapillary venules called high endothelial venules (HEVs). Interactions of T cell-expressed L-selectin (CD62L) and CC-chemokine receptor 7 (CCR7) with peripheral node addressin (PNAd) and CCL19 expressed on HEVs mediate the rolling and attachment of T cells to HEVs. The binding of lymphocyte function-associated antigen-1 (LFA-1) with intercellular adhesion molecule-1 (ICAM-1) initiates the transendothelial migration of T cells to the paracortical region of draining lymph nodes, where both naïve T cells and Tregs interact with antigen-presenting cells (APCs). CCR7-CCL19/CCL21 interactions are necessary for the motility of T cells within the draining lymph node to scan APCs for alloantigen presentation. T cell receptor activation, which occurs upon naïve T cell interaction with APCs, results in upregulation of CD69 by T cells. CD69 prevents the surface expression of sphingosine-1 phosphate receptor (S1PR) on T cells, rendering T cells desensitized to the S1P gradient, which in normal conditions drives T cells out of the draining lymph nodes. Activated T cells undergo clonal expansion and differentiate into effector CD4⁺ IFNγ⁺ Th1 cells. Tregs suppress allosensitization by inhibiting APC or T cell activation in the draining lymph nodes. (II) Upregulation of S1PR in conjunction with downregulation of CCR7 and L-selectin (CD62L) lymphoid homing molecules drive T cells out of the draining lymph node in response to high levels of S1P chemoattractant in the blood vessels. Antigen-primed Th1 cells express high levels of chemokine receptors, CCR1, CCR2, CCR3, and CCR5, which direct them to migrate towards the inflamed cornea in response to high chemokine gradient of peripheral tissue-specific chemokines including CCL2, CCL3, CCL4, CXCL10/IP-10, and CCL5/RANTES. (III) Th1 cells move within the blood vessels and migrate towards the corneal graft through interactions of E-selectin and P-selectin expressed by endothelial cell layer of vasculature with T cell-expressed ligands, glycosylated CD43, and PSGL-1. Arrest and subsequent transendothelial migration of effector Th1 cells towards the graft tissue are mediated through interactions of very late antigen-4 (VLA-4) and LFA-1 expressed on T cells with ICAM-1 and VCAM-1 selectins, which are highly expressed by endothelial cells of the blood vessels. This cascade of interactions collectively results in the migration of effector CD4⁺ IFNγ⁺ Th1 cells to the graft tissue, where they mount a delayed type hypersensitivity response against the allogeneic corneal graft.