Beyond migration—Chemokines in lymphocyte priming, differentiation, and modulating effector functions

Abstract

Chemokines and their receptors coordinate the positioning of leukocytes, and lymphocytes in particular, in space and time. Discrete lymphocyte subsets, depending on their activation and differentiation status, express various sets of chemokine receptors to be recruited to distinct tissues. Thus, the network of chemokines and their receptors ensures the correct localization of specialized lymphocyte subsets within the appropriate microenvironment enabling them to search for cognate antigens, to become activated, and to fulfill their effector functions. The chemokine system therefore is vital for the initiation as well as the regulation of immune responses to protect the body from pathogens while maintaining tolerance towards self. Besides the well investigated function of orchestrating directed cell migration, chemokines additionally act on lymphocytes in multiple ways to shape immune responses. In this review, we highlight and discuss the role of chemokines and chemokine receptors in controlling cell-to-cell contacts required for lymphocyte arrest on endothelial cells and immunological synapse formation, in lymphocyte priming and differentiation, survival, as well as in modulating effector functions.

Fates of CD8+ T cells in Tumor Microenvironment

“…Matsumura and colleagues observed mice deficient of CXCR6, the receptor for CXCL16 is lowly expressed on the surface of T cells; and discovered that these mice exhibited decreased T cell migration, poor anti-tumor immunity and prognosis in breast cancer [ 55 ]. The expression of CCL4 was observed to be directly proportional to the expression of CD8, Gzmb and the infiltration of CD8+ T cells [ 55 , 56 ]. CCR5 is the common receptor for CCL4 and CCL5; CCL20 binds to its receptor CCR6; and CCL3 to its receptor CCR1 [ 56 ].…”

“…The expression of CCL4 was observed to be directly proportional to the expression of CD8, Gzmb and the infiltration of CD8+ T cells [ 55 , 56 ]. CCR5 is the common receptor for CCL4 and CCL5; CCL20 binds to its receptor CCR6; and CCL3 to its receptor CCR1 [ 56 ]. Reportedly CCL2, one of the most common chemokines in the TME of various cancers, is secreted in response to the production of ROS and RNS by MDSCs in the TME [ 29 ].…”

“…CD69, CD95 and OX40 are costimulatory molecules commonly expressed on CD8+ T cells that bind to corresponding ligands that are expressed on DCs. The successful binding of these costimulatory molecules to their respective ligands leads to the activation of CD8+ T cells, thereby promoting tumor cell death [ 55 , 12 , 56 ]. CD69 activation stimulates the influx of calcium ions (Ca 2+ ) and the activation of extracellular kinases ERK1/2 there-by facilitating CD8+ T cell proliferation.…”

Role of Mechanotransduction and Tension in T Cell Function

“…T cell tethering and rolling eventually leads to arrest and firm adhesion on endothelial cells, which is driven by heterodimeric integrins and their ligands and which also requires low force from the blood flow ( 2 , 13 , 16 ). Remarkably, integrin adhesiveness is increased very shortly after T cells make contact with endothelial cells, through a multistep process during which force plays an essential role ( 17 ).…”

The role of chemokines and chemokine receptors in multiple sclerosis

“…Many chemokines that are produced locally in the tissue, attract different kinds of leukocytes to the sites of infection and inflammation via selective receptors [10]. Chemokines could induce and activate leukocyte adhesion molecules, establishing a chemotactic concentration gradient that causes transendothelial monolayer recruitment [64,110]. The induction of proteolytic enzymes promotes the opening of the BBB and mediates the retention of leukocytes in the central nervous system.…”