CXCR5

Although the help of T cells to B cells was described several decades ago, it was the discovery of the expression of CXCR5 by follicular B helper T cells (Tfh cells) and the subsequent discovery of their dependence on BCL6 that led to the recognition of Tfh cells as an independent helper subset.

Tfh cells prime B cells to elicit extrafollicular and follicular (germinal center) antibody responses and are critical for affinity maturation and maintenance of humoral memory. In addition to the role that Tfh cells play in antimicrobial defense, cancer and as HIV reservoirs, regulation of these cells is critical to prevent autoimmunity.

CXCR receptors (C-X-C Motif Chemokine Receptors) are a family of chemokine receptors that belong to the group of G-protein-coupled receptors (GPCRs). There are currently 8 known chemokine receptors. These are transmembrane, G-protein-coupled receptors that are activated by the binding of one or more chemokines.

CXCR receptors play an essential role in the immune system by influencing the migration of immune cells to sites of inflammation or to tissues. Chemokines are signaling molecules produced by various cells. They form a family of chemoattractive molecules, of which more than 50 have been identified to date. Chemokines are categorized into four main groups according to the number and spacing of conserved cysteines: CXC, CC, CX3C and C. They bind to their specific receptors (e.g. CXCR) and thus initiate a signaling cascade that controls the behavior of immune cells, including their movement, activation and differentiation. In individual cases, this can also influence tumor growth.

CXCR5 (acronym for CXC motif chemokine receptor 5) is a receptor protein from the chemokine receptor family. The receptor protein is encoded by the CXCR5 gene of the same name (C-X-C Motif Chemokine Receptor 5), which is localized on chromsome 11q23.3. The CXCR5 receptor type is found in particular on lymphocytes (B and T lymphocytes) and can be detected in particularly high density on Burkitt's lymphoma cells. CXCR5 is activated by a cytokine, the CXC motif chemokine CXCL13 (BCA-1), and plays an important role in the targeted attraction (chemotaxis) of B cells.

Chemokines, a subgroup of cytokines, are small (size between 8 and 10 kDa), chemotactically active proteins (signal proteins). They are common in all vertebrates, in some virus species and bacteria. In humans, about 50 chemokines are currently known. A highly conserved structural feature of all chemokines is a fixed group of cysteine residues stabilized by 1 or 2 disulfide bridges. This key structural position in the molecule is responsible for their fixed 3-dimensional structure (see Chemokines below).

In CC chemokines the cysteines follow each other directly, in CXC chemokines (see figure) they are separated by 1, in CXXXC chemokines by 3 other amino acids. Chemokines are produced and secreted by a variety of immune cells. They mediate their signals by means of specific chemokine receptors via G-proteins. Some chemokines have proinflammatory effects, while others have regulatory effects in tissue formation and homeostasis.

Increased chemokine expression is found in chronic inflammatory diseases such as HIV infection, atopic eczema, bronchial asthma, allergic rhinitis and psoriasis vulgaris. Chemokines play a positive role, for example, in wound healing, haematopoiesis (blood formation) or the defence against infections. The fact that chemokine receptors are not only present on inflammatory cells but also on tumor cells and endothelial cells suggests that they are also involved in the migration of tumor cells or the metastatic behavior of the various tumors.

CXCR5 is expressed on the majority of memory CD4 T cells in the follicles of inflamed tonsils. T follicular helper (Tfh) cells, a CD57+ subset of CXCR5+ T cells,lack CCR7, which allows them to move from the T zone to the follicles after activation, where they support B cell maturation and antibody production. Conversely, B cells activated by antigen in follicles upregulate CCR7 and move toward the T cell zone.

CXCR4 signaling is also important for the migration of naive and memory B cells to germinal centers. CCR5 ligands can direct naive CD8 T cells to sites of CD4 T cell-DC interaction in lymph nodes.

1. Chen Yet al. (2019) CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance. Nat Commun 10: 4415.
2. Li H et al. (2015) CD25(+) Bcl6(low) T follicular helper cells provide help to maturing B cells in germinal centers of human tonsil. Eur J Immunol 45: 298-308.
3. Vinuesa CG et al (2016) Follicular Helper T Cells. Annu Rev Immunol 34:335-368.