Integrin function in T-cell homing to lymphoid and nonlymphoid sites: getting there and staying there

Abstract

The continuous recirculation of naive T cells and their subsequent migration to tissue following activation is crucial for maintaining protective immunity against invading pathogens. The preferential targeting of effector and memory T cells to tissue is instructed during priming and mediated by cell surface expressed adhesion receptors such as integrins. Integrins arc involved in nearly all aspects of T-cell life, including naive T-cell circulation, activation, and finally effector T-cell trafficking and localization. Recent research has revealed that microenvironmental factors present during T-cell priming result in the specific regulation of adhesion/integrin and chemokine receptor expression. Once antigen-experienced T cells enter tissue, further changes in integrin expression may occur that arc critical for T-cell localization, retention, effector function, and survival. This review discusses the function of integrin expression on T cells and the multiple roles integrins play on naive T cells and in directing effector T-cell trafficking to nonlymphoid sites in order to maintain protective adaptive immunity at body barriers.

FIGURE 1. T cell integrin expression and their ligands

Naïve CD4 and CD8 T cells express low levels of the αLβ2 (LFA-1), α4β1 (VLA-4) and α4β7 (LPAM) integrins. In the extended, high affinity state, these integrins bind to ICAM-1, VCAM-1, and MAdCAM-1 expressed on antigen presenting cells (APC) or the vascular endothelium. These integrin ligands are members of the Immunoglobulin (Ig) superfamily and are composed of several Ig domains represented by the circular repeats composing their structure. Of note, MAdCAM-1 also contains a mucin-like domain that is capable of binding CD62L.

FIGURE 2. Specific LN microenvironments lead to the acquisition of preferential homing of T cells to the small intestine, the skin, and the brain

Naïve T cells enter into lymph nodes (LN) via their well characterized interaction with the vascular high endothelial venules. In the mesenteric LN (mLN) or Peyer’s patch (PP) of the small intestine (SI), naïve T cells bind to MAdCAM-1 and ICAM-1 via CCR7-activated α4β7 and αLβ2 integrins. (A). Antigen-laden αE (CD103) integrin-positive dendritic cells (DCs) migrate from the SI parenchyma into the mLN (A1). During T cell priming, these αE integrin-positive DCs produce an active metabolite of vitamin A, all-trans retinoic acid (ATRA), that induces expression of molecules involved in homing to the SI, α4β7 integrin and CCR9 (A2). These ‘gut’ homing T cells then exit the mLN and preferentially circulate to the SI via interaction between α4β7/MAdCAM-1 and CCR9/CCL25 (A3). (B). Skin derived DCs transport antigen to the local skin draining lymph node (B1). Skin draining DCs are believed to produce 1,25 dihydroxy-VitD3 (1,25VitD3) from Vitamin D present in the skin. The presence of 1,25VitD3 during T cell priming results in the upregulation of skin homing molecules (CCR10) and suppression of the induction of gut homing molecules such as α4β7 and CCR9 (B2). Other skin homing molecules are also induced by other unknown factors. These ‘skin’ homing T cells then exit the pLN and preferentially circulate to the skin via interactions between αLβ2/ICAM-1, CCR10/CCL27, and P-selectin ligand (P-lig)/P-selectin (B3). (C). The mechanism by which antigen reaches the cervical LNs (cLNs) is poorly defined, but may involve migration of brain derived DCs, other antigen presenting cells (APCs), or direct drainage (C1). T cells responding to brain-derived antigens upregulate α4β1 and become α4β7low (C2). The factors involved in this process are entirely unidentified. These ‘brain’ homing T cells then exit the cLN and preferentially enter the brain via interactions between α4β1/VCAM-1 (C3).

FIGURE 3. Integrin expression induction and function in non-lymphoid tissue

Following entry into non-lymphoid sites such as the small intestine (A) or the brain (B), T cell integrin expression is altered by microenvironmental factors of the tissue. (A). α4β7 integrin high cells enter through venules of the small intestine expressing MAdCAM-1. Upon entry into the small intestine, CCR9 positive CD8 T cells migrate through the lamina propria to reach the collagen IV-rich basement membrane of the epithelium. Here, in a TGF-β dependent fashion, T cells downregulate α4β7 integrin and upregulate α4β7 integrin (A1). CCR9 binds CCL25 present on the small intestinal epithelial cells, triggering α4β7 integrin-dependent adhesion to E-cadherin expressed on the epithelial cells (A2). α1β1 integrin is believed to interact with collagen IV, further promoting retention/survival of the intraepithelial lymphocytes (IELs) (A3). (B.) α4β1 integrin high CD8 T cells gain entry into the brain parenchyma through a high affinity interaction with VCAM-1 expressed on inflamed venules. Brain tumor infiltrating T cells are hypothesized to encounter TGF-β which is abundant in the tumor microenvironment. This results in the upregulation of α4β7 integrin (B1). Cognate interactions between the TCR and peptide/MHC class I on E-cadherin positive tumor cells is believed to result in α4β7 integrin binding to E-cadherin in the immune synapse (B2). This interaction results in the polarization and release of cytotoxic granules containing perforin and granzyme B (cytotoxins) and the killing of tumor cells (B3).