Functional Insights From Immunoreceptor Structures

Abstract

Generation of immunity is a complex process orchestrated by various immune cells upon recognition of a diverse range of foreign molecules. It has two arms, namely innate and adaptive immunity. The former is the first responder that triggers a non-specific immune response and relies on various cells, including phagocytes, dendritic cells, and Natural Killer cells. The latter is an antigen-specific response and involves T cells and B cells. Innate immunity depends on pattern recognition receptors expressed on the surface of participating cells, including Toll-like receptors, Nod-like receptors, and C-type lectin receptors, whereas adaptive immunity involves specific cell surface receptors like T cell receptors and B antigen cell receptors.

The initial step in the adaptive immune response involves antigen-presenting cell binding, processing, and display of the antigens, which are then recognized by T and B cell antigen receptors, leading to the formation of antigen-receptor complexes on the cell surface. Decades of research have focused on understanding the intricate molecular-level details of this interaction, with the ultimate goal of designing therapeutics that target them. In this regard, structural biology has been an invaluable tool in providing the molecular blueprint of these ligand-receptor interactions.

In this special issue, 14 reviews have been written by leading research groups in the field. These detail the advancements emerging from structural studies, ranging from how T cell receptors (TCRs) become activated, antigen–antibody interactions, to understanding the SARS-CoV-2 receptor binding domain. This review addresses recent structural breakthroughs and concepts in T cell signaling and T cell biology, including unconventional T cells, namely γδ T cells, Mucosal-associated invariant T cells (MAIT cells), integrin receptors, and cytokine binding receptors. Collectively, a broad range of receptor-ligand interactions central to immunity are covered in this issue (Figure 1).

T cells play a crucial role in antigen-specific immune responses through their surface-expressed antigen receptors known as TCRs. They either belong to αβ or γδ T cell lineages, and comprise two chains with variable and constant domains that resemble an immunoglobulin architecture. In recent years, T cell-targeted therapies have shown promise for treating cancer, autoimmunity, and infectious diseases. Success in development of the therapeutics requires in-depth knowledge of receptor structure–function relationships as well as T cell biology. In line with this, Baker and his team [1] highlight the importance of emerging TCRs that do not abide by the usual established recognition patterns based on structural information. Therefore, as TCR diversity continues to expand, it is paramount to have a thorough understanding of T cell immunity in order to fully harness the immunomodulatory potential of T cells. Davis and colleagues [2] explore the molecular mechanisms underpinning the initial TCR cell signaling events, focusing on microvilli, known as ‘close contacts’ that are stabilized by the small adhesion protein CD2 and its ligand, CD58. Alongside, they provide a wealth of information about accessory protein receptors, including CD28, CTLA-4 and PD-1, and discuss their amplifying or suppressing roles in TCR signaling.

Schamel and Alarcon [3] have prepared a review discussing the allosteric changes that occur during TCR binding to peptide–MHC (pMHC) complexes and how the TCR signal is transduced from the antigen-binding loops to the CD3 multisubunit complex, leading to T cell activation. Willcox and colleagues [4] provide a detailed review of phosphoantigen sensing by γδ T cell subsets, particularly the Vγ9Vδ2 T cells, which are highly prevalent in humans, and discuss the regulatory role of the butyrophilin family of proteins alongside their function as antigen-presenting molecules.

Reinherz and his team [5] elegantly summarize the molecular mechanisms underlying the mechanotransduction phenomenon that occurs when the TCR engages with the pMHC complex and initiates a signal cascade leading to T cell activation. With recent advancements in structural immunology, understanding the mechanosensing paradigm will guide CAR-T cell design to achieve effective T cell signaling for therapeutic applications. Finally, in this section, Rossjohn and his team [6] address the structural landscape of MR1 (a non-classical MHC-class I-like molecule) ligands to better understand how different small metabolite by-products from bacteria are recognized by a diverse repertoire of MR1-reactive T cells.

Cytokines are small, soluble protein ligands that assist in cell-to-cell communication, playing a role in the body's immune and inflammatory responses. Using structural biology and biophysical approaches, Lopez and Parker's teams [7] summarize the recent advancements in studies of the β common cytokine receptor family, including IL-3, IL-5, and GM-CSF, and their signaling mechanisms, informing the design of effective therapeutics.

Arnaout's [8] review details the structures of cell-adhesion proteins, known as integrins and their ligands, providing an in-depth treatise of how to modulate their therapeutic function in inflammatory and autoimmune settings. Another review authored by Luca [9] discusses the biology and recent advancements of Lymphocyte activation gene-3, an immune checkpoint inhibitory receptor approved as a potent therapeutic target in treating various cancers.

Development of vaccines against infectious diseases such as smallpox and polio provided a significant contribution in eradicating those diseases globally. In accordance with this, reviews in this section discuss the advancements in the development of new vaccine strategies for diseases emerging in recent times. Julien and colleagues [10] summarize the bottlenecks in the Plasmodium parasites lifecycle and transmission, detailing an innovative therapeutic design of next-generation vaccines to combat malaria. Wilson and his team [11] highlight the emergence of SARS-CoV-2 variants, detailing the role of structural proteins involved in the coronaviruses' lifecycle and the development of escape-resistant antibodies. This review provides a comprehensive overview of the various domains of the spike protein that could be targeted for developing potential neutralizing antibodies. Another interesting review by Gao and team [12] outlines the advancements in the SARS-CoV-2 virus from the T cell biology perspective, covering in detail the MHC molecules involved, binding peptides, identified epitopes, and respective TCR engagement to address the immune escape mechanisms displayed by the virus.

Mariuzza and his team [13] provide a comprehensive review of advancements in the structural aspects of NK receptors and their ligands of tumor and viral origin, detailing how NK cell cytotoxicity is regulated. McMichael and colleagues [14] dive deep into HLA-E biology, a dimorphic antigen-presenting molecule, including the identification of pathogen-derived bacterial and viral binding peptides and the structural insights into various HLA-E-peptide receptor complex structures.

This is a remarkable era for advances in the field of structural immunology. Findings of immunoreceptor structure–function relationships compiled in this special issue of Immunological Reviews shed light on various receptors, including their function, ligands, recognition mechanisms, and how this knowledge can be translated for our therapeutic gain. Additionally, the information discussed on antigen–antibody interactions, in the context of COVID-19 and malaria, widens our understanding of the potential of future vaccine design to treat these diseases. Thus, the progress toward developing novel therapies and biologics is promising, with the impressive emerging body of structural biology work on immune receptors.

The authors declare no conflicts of interest.