Mechanisms of T cell organotropism

Abstract

Protective immunity relies upon T cell differentiation and subsequent migration to target tissues. Similarly, immune homeostasis requires the localization of regulatory T cells (Tregs) to the sites where immunity takes place. While naïve T lymphocytes recirculate predominantly in secondary lymphoid tissue, primed T cells and activated Tregs must traffic to the antigen rich non-lymphoid tissue to exert effector and regulatory responses, respectively. Following priming in draining lymph nodes, T cells acquire the 'homing receptors' to facilitate their access to specific tissues and organs. An additional level of topographic specificity is provided by T cells receptor recognition of antigen displayed by the endothelium. Furthermore, co-stimulatory signals (such as those induced by CD28) have been shown not only to regulate T cell activation and differentiation, but also to orchestrate the anatomy of the ensuing T cell response. We here review the molecular mechanisms supporting trafficking of both effector and regulatory T cells to specific antigen-rich tissues.

Keywords: Homing receptors; Organotropism; T cell migration; T lymphocytes.

Fig. 1

Memory T cell tissue homing. Memory T lymphocytes acquire the expression of homing receptors, imprinted during priming in the draining LNs, which enable their migration to specific tissues. T cells trafficking to the heart occurs due to the expression of C-met which binds to its ligand HGF released by the heart. This binding induces the upregulation of CCR4 and CXCR3. The interaction of α4β7 and CCR9 with their respective ligands MAdCAM-1 and CCL25 results in gut specific homing. Migration into the skin occurs due to the expression of CCR4, CCR10, α4β1 and CLA which interact with their respective ligands CCL17, CCL27, VCAM-1 and E-selectin on the endothelium. Th1 cell homing to the liver is been reported to use VLA-4 and CCR5 whereas Th2 cells use VAP-1 which is expressed on hepatic venules and liver sinusoids. CCL3 which binds to CCR3 and CCR4 have been shown to contribute to imprinting a lung homing signature. At the end of an immune reaction some T lymphocytes become tissue resident following upregulation of CD69 and CD103

Fig. 2

Regulatory T cell tissue homing. Modulation of immune responses by Tregs requires appropriate trafficking and retention. Homing signatures are mediated by distinct chemokine and adhesion molecules. Activated Tregs are predisposed to retention in the periphery due to the interaction of α_Eβ₇ with E-cadherin. Tregs expressing α₄β₇ and CCR9 migrate to the intestines. A subset of activated Tregs up-regulate CXCR4 expression and become responsive to SDF-1, enabling them to migrate to the bone marrow. Treg homing to the inflamed liver is mediated by interactions of the Tregs with hepatic sinusoidal endothelial cell expression of CLEVER-1. CCR4 expression is associated with the recruitment of Tregs in heart allograft of tolerant mice. Similar to effector T cells, Tregs express the skin-homing receptors CLA and CCR4 that bind to E-selectin and CCL17 respectively