The Multi-Functional Roles of CCR7 in Human Immunology and as a Promising Therapeutic Target for Cancer Therapeutics

Abstract

An important hallmark of the human immune system is to provide adaptive immunity against pathogens but tolerance toward self-antigens. The CC-chemokine receptor 7 (CCR7) provides a significant contribution in guiding cells to and within lymphoid organs and is important for acquiring immunity and tolerance. The CCR7 holds great importance in establishing thymic architecture and function and naïve and regulatory T-cell homing in the lymph nodes. Similarly, the receptor is a key regulator in cancer cell migration and the movement of dendritic cells. This makes the CCR7 an important receptor as a drug and prognostic marker. In this review, we discussed several biological roles of the CCR7 and its importance as a drug and prognostic marker.

Keywords: CC-chemokine receptor 7; CCL19; CCL21; drug target; immune tolerance; prognostic marker.

FIGURE 1

Stepwise mechanism of lymphocyte homing to the lymph nodes. The T-cells when emerging from the blood enter the peripheral lymph nodes through the tethering and rolling mechanism, activation of CCR7, firm arrest, and transendothelial migration. At first, L-selection of lymphocyte binds with peripheral node addressins (PNAd) and sialomucins on high endothelial venules (HEVs). The interaction results in T-cell attachment to HEVs and results in cell rolling. The rolling cells then interact with CCL21/CCL19 and thus are immobilized by glycosaminoglycans (GAGs). The signals from CCR7 and blood flow force induce conformational changes in α_Lβ_2-integrins, thus allowing firm binding to intracellular addressin cell adhesion molecular 1 (ICAM1) and ICAM2. CCR7 also activates α_Lβ_2-integrin mucosal addressin cell-adhesion molecule 1 (MAdCAM) (Förster et al., 2008).

FIGURE 2

CCR7-mediated tolerance in response to inhaled antigens. The dendritic cells enter the lungs and produce interstitial and bronchial dendritic cells. The bronchial dendritic cells carry the antigens and upregulate the CCR7 and move toward lymphatic vessels to activate CCL21. The dendritic cells are passively transported into the draining lymph node. The dendritic cells then present antigens to the naïve T-cells and via endothelial venules, the T-cells penetrate into the lymph node. Migration of T-cells on reticular cells results in expression of CCL19/21.

FIGURE 3

Functioning of CCR7 in regulatory T-cells. Almost all regulatory T-cells express CCR7 and use it for entering into lymph nodes. These cells homing to the lymph node allow their interaction with the antigens on the dendritic cells. As a result, the regulatory T-cells proliferate and expand upon presentation with the antigen. (A) Interfere with naïve T helper cell proliferation, (B) low number effector cells and inhibits differentiation, (C) regulatory T-cells exert suppressive activities by targeting dendritic cells, and (D) T-cells. (E) naive T cell conversion to regulatory T cells in the presence of low amount of antigens.

FIGURE 4

Role of CCR7 in the migration of thymocytes. Thymocyte progenitors derived from bone marrow travel to the thymus. As the CD4/8 lacks expression, the cells are known as double-negative cells. The DN1 cells differentiate at the thymic entry site, and transformation to DN2 occurs in the mid cortex. The DN3 thymocyte differentiation happens while cells migrate to the outer cortex and developed into DN4 cells in the sub-capsular zone. The double-negative dendritic cell transition to the double-positive phase is accomplished in reverse migration and the double-positive thymocytes enter the medulla. In the medulla, positively double-positive cells mature and result in the production of CD4⁺/CD8⁺. A small population of double-positive cells expresses CCR7 and might drive the migration of double-positive cells to the medulla from the cortex. The CCR7 also plays a key role in mature single positive CD62L cells and guides the maturation of these cells. In this period, thymocytes interact with dendritic cells and medullary and thymic epithelial cells, deleting auto-reactive thymocytes and guiding positive selection.