CXCR5, the Defining Marker for Follicular B Helper T (TFH) Cells

The discovery of follicular B helper T (TFH) cells has its roots in the early 90s, the “childhood” of chemokine research that has since grown into an independent, global specialty within immunology. The class of chemoattractant proteins with shared structural features was named “chemokines,” and early work with non-chemokine (FMLP, C5a) and chemokine (IL-8/CXCL8) receptors revealed that chemokine receptors belong to the large family of G-protein-coupled receptors (GPCRs) distinguished by their prototypical seven-transmembrane protein architecture. The search for novel chemokines and their receptors greatly intensified during that time, because it became increasingly clear that this novel cytokine system is essential for controlling immune cell mobilization and tissue localization and, hence, for controlling the entirety of immune processes in health and disease. Molecular identification of chemokine receptors led to the identification of immune cells that responded to the corresponding chemokine ligands and allowed their tracking during acute and chronic immune responses. At the last count, the inventory of chemokine receptors that, together with adhesion receptors, make up the address codes on human immune cells includes 18 individual members recognizing one or multiple of a total of 45 chemokines. Further underscoring the complexity of the chemokine system, we also know of six atypical chemokine receptors, some of which control chemokine positioning and degradation. Sincemy earliest steps in research, I was fascinated by the cytokine network controlling the highly complex interactions between immune cells and their functions in immune defense. In fact, an ambitious project aimed at the molecular characterization of the elusive “antigen-specific T helper factors” tipped the balance in favor of carrying outmy Ph.D. studies in the lab of Profs. D. G. Kilburn, R. C. Miller Jr., and R. A. J. Warren at the University of British Columbia in Vancouver. It was not the skiing in the Whistler Mountains nor the salmon fishing along the Sunshine Coast that did the job, as suggested by some of my colleagues at the Federal Institute of Technology in Zurich. Needless to say that the molecular identification of the T cell antigen receptor in 1984 brought our project to an immediate halt. Still, when the question about postdoc projects arose, I was fascinated by the new world of chemotactic cytokines (to be called “chemokines” a few years later) that I was introduced to by Prof. Marco Baggiolini, the director at the Theodor-Kocher Institute of the University of Bern. Therefore, upon arrival at the Theodor-Kocher Institute in 1989, I was determined to clone the receptor for NAF, the first chemokine with selectivity for neutrophils (now known as IL-8 or CXCL8 according to the systematic chemokine nomenclature). This young field of research turned out to be highly competitive, not least because of its translational potential. Unsurprisingly, we were beaten by two labs who reported the cloning of the CXCL8 receptors well before our own initiative had a chance to take off (1, 2). As a small consolation, we succeeded to be first in demonstrating that human neutrophils carried two types of CXCL8 receptors on their cell surface distinguished by their variable affinity for other CXCL8-related chemokines (3, 4). Still, our multipronged cloning efforts paid off and revealed numerous orphan GPCRs with similarity to the CXCL8 receptors. In a great team effort by many colleagues, including Marcel Loetscher, Daniel Legler, Patrick Schaerli, and Regula Stuber-Roos, together with the protein chemist Ian Clark-Lewis at the Biomedical Research Centre of the University of British Columbia (who sadly died in 2002), we were