Introduction: Signaling and signal diversification in antigen‐specific immune cells

In the past 50 years, technological developments and intensive basic research have enabled substantial progress in our understanding of how the normal immune system works, how it participates in the pathophysiology of human diseases such as autoimmunity and immunodeficiencies, and how it can be pharmacologically influenced to combat diseases such as cancer, autoimmunity, inflammation, and infections. Arguably, the most detailed comprehension of the immune system concerns the activation and development of T cells and B cells, which collectively stipulate antigen-specific immunity, by way of antigen-specific helper or cytotoxic T cells and antigen-specific antibody-producing B cells. Beginning with the identification and gene cloning of the antigen receptors on T cells and B cells, research in this area has led to the characterization of multiple other receptors that diligently fine-tune the activation and development of T cells and B cells, including co-receptors, co-stimulatory receptors, and co-inhibitory receptors (Figure 1). Similarly, the intracellular signal transduction machineries coupling these receptors to cellular responses have been significantly elucidated. Mechanisms enabling diversification and specification of intracellular signals have been identified. More recent work, which has been facilitated by developments in microscopy technology and biophysical assays, has yielded an increasingly more detailed appreciation of the organization of signaling mechanisms at the molecular level, both in space and in time. A clearer picture of how alterations in these molecular pathways are linked to human diseases has ensued. In this issue of Immunological Reviews, leaders in the field review the literature and provide insights regarding various aspects of signal transduction and diversification in T cells and B cells. First, three reviews deal with the mechanisms by which engagement of the T-cell antigen receptor (TCR) and other immune receptors leads to signal initiation. Wolgang Schamel (Freiburg, Germany) and collaborators review the main models of TCR conformational regulation. In essence, they converse on the current hypotheses regarding how ligand binding to the TCR changes the structure of the associated CD3-ζ subunits. A unifying model is proposed. Etienne Gagnon (Montréal, Québec, Canada) and his colleague review the importance of electrostatic interactions in assembly, maintenance of inactive state, triggering and signaling by immune receptors, with a special emphasis on T cells. They discuss how the cytoplasmic domains of TCR subunits interact with charged lipids in the plasma membrane, and how these interactions are regulated in order to influence TCR signal initiation and strength. Furthermore, Enfui Hui (San Diego, CA, USA) and his collaborators review recent inroads into T-cell signaling that have been provided by membrane reconstitution analyses. Notably, their own work has led to key new insights into how the inhibitory immune checkpoint receptor programmed death-1 controls T-cell activation. Next, two reviews focus on the mechanisms involved in amplification of antigen receptor-driven signals. Claire Hivroz (Paris, France) and her colleagues review how TCR signaling is amplified and diversified in the endocytic compartment. They present data showing that the transmembrane adapter linker for activation of T cells (LAT) is shuttled between endocytic compartments and the immune synapse during T-cell activation to provide signal amplification. Likewise, Wanli Liu (Beijing, China) and collaborators examine how the phospholipid phosphatidylinositol (PI) 4,5-bisphosphate (PIP2) amplifies B-cell antigen receptor (BCR)-driven signals in B cells. Based on the studies discussed, the authors propose a “gasoline engine model” for amplification of B-cell activation. They also review data showing the potential broad applicability of this model to other receptor signaling systems. In addition to antigen receptors, multiple other receptors and intracellular signaling molecules play essential roles in T-cell and B-cell activation and development. Four reviews cover specific aspects of this topic. Inducible costimulator (ICOS) is a receptor expressed on T cells that plays a critical role in co-stimulation. Woong-Kyung Suh (Montréal, Québec, Canada) and his team discuss in detail the roles, mechanisms of action, and signaling mechanisms of ICOS in immune cells, not only in follicular T-helper (TFH) cells but also in other cell types. The authors also compare the functions and signaling mechanisms of ICOS with those of the related receptor CD28. Ion channels, including the calcium release-activated channel (CRAC), have been broadly implicated in lymphocyte functions. Bebhinn Treanor (Toronto, Ontario, Canada) and colleagues review how these channels regulate B-cell activation and development. They discuss not only calcium channels such as CRAC, but also chloride, potassium, and other types of ion channels. The Cbl proteins are ubiquitin ligases implicated in ubiquitination and degradation of several components of the antigen receptor signaling machinery in T cells and B cells. Hua Gu (Montréal, Québec, Canada) and his colleagues review accumulating data showing the broad range of molecular targets for the Cbl proteins in T cells and B cells, allowing the Cbl proteins to be gatekeepers of T-cell activation, B-cell development, and the germinal center reaction. Lastly, Jeroen Roose (San Francisco, CA, USA) and his collaborators review recent data showing how more downstream effectors of T-cell activation, such as mammalian target of rapamycin and other kinases, are regulated to control T-cell activation. The involvement of these kinases in mRNA translation, metabolic adaptation, and tonic signaling is also discussed. Last, three reviews deal with how alterations in components of the antigen receptor signaling machinery in T cells, B cells, or both have been broadly implicated in the pathophysiology of human diseases. Pamela Schwartzberg (Bethesda, MA, USA) and her team show that activating mutations in PI 3′ kinase in humans result in altered T-cell and B-cell functions, thereby causing a range of clinical manifestations including immunodeficiency and autoimmunity. In a related way, Sylvain Latour (Paris, France) and his collaborators examine how mutations in a broad array of components of the T-cell signaling apparatus can cause immunodeficiencies in humans, especially upon infection by Epstein-Barr virus. Some of these mutations affect proteins required for T-cell cytotoxicity, while others involve polypeptides needed for T-cell proliferation. Finally, Louis Staudt (Bethesda, MD, USA) and colleagues underscore how activating mutations in the BCR signaling machinery are implicated in human B-cell malignancies. They discuss compelling clinical data showing that inhibitors of the mutated molecules can be used to treat effectively these diseases. Altogether, this monograph by leading scientists underscores the extensive progress that has been made through basic research in understanding how activation and development of T cells and B cells is controlled at the molecular level. It also clearly shows that alterations in the T-cell or B-cell signaling apparatus are implicated in human diseases. Furthermore, it indicates that dysregulated components of this machinery can be targeted to treat human pathologies. Nonetheless, while progress in this research area has been enormous over the past 50 years, it is clear that much more work in the future is needed to comprehend fully the processes involved, in order to use best the information provided for understanding and treating human diseases. This work was supported by grants from the Canadian Institutes of Health Research (CIHR) MT-14429, MOP-82906, FDN-143338 to AV. AV also receives a contract from Bristol Myers-Squibb to study the mechanism of action of anti-SLAMF7 monoclonal antibody elotuzumab in multiple myeloma. AV holds the Canada Research Chair on Signaling in the Immune System. The authors declare no conflict of interest.

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