Instructive Cues of Thymic T Cell Selection.

A high diversity of αß T cell receptors (TCRs), capable of recognizing virtually any pathogen but also self-antigens, is generated during T cell development in the thymus. Nevertheless, a strict developmental program supports the selection of a self-tolerant T cell repertoire capable of responding to foreign antigens. The steps of T cell selection are controlled by cortical and medullary stromal niches, mainly composed of thymic epithelial cells and dendritic cells. The integration of important cues provided by these specialized niches, including (a) the TCR signal strength induced by the recognition of self-peptide-MHC complexes, (b) costimulatory signals, and (c) cytokine signals, critically controls T cell repertoire selection. This review discusses our current understanding of the signals that coordinate positive selection, negative selection, and agonist selection of Foxp3+ regulatory T cells. It also highlights recent advances that have unraveled the functional diversity of thymic antigen-presenting cell subsets implicated in T cell selection.

Dendritic Cell Regulation of T Helper Cells.

As the professional antigen-presenting cells of the immune system, dendritic cells (DCs) sense the microenvironment and shape the ensuing adaptive immune response. DCs can induce both immune activation and immune tolerance according to the peripheral cues. Recent work has established that DCs comprise several phenotypically and functionally heterogeneous subsets that differentially regulate T lymphocyte differentiation. This review summarizes both mouse and human DC subset phenotypes, development, diversification, and function. We focus on advances in our understanding of how different DC subsets regulate distinct CD4+ T helper (Th) cell differentiation outcomes, including Th1, Th2, Th17, T follicular helper, and T regulatory cells. We review DC subset intrinsic properties, local tissue microenvironments, and other immune cells that together determine Th cell differentiation during homeostasis and inflammation.

Transcriptional and Metabolic Control of Memory B Cells and Plasma Cells.

For many infections and almost all vaccines, neutralizing-antibody-mediated immunity is the primary basis and best functional correlate of immunological protection. Durable long-term humoral immunity is mediated by antibodies secreted by plasma cells that preexist subsequent exposures and by memory B cells that rapidly respond to infections once they have occurred. In the midst of the current pandemic of coronavirus disease 2019, it is important to define our current understanding of the unique roles of memory B cells and plasma cells in immunity and the factors that control the formation and persistence of these cell types. This fundamental knowledge is the basis to interpret findings from natural infections and vaccines. Here, we review transcriptional and metabolic programs that promote and support B cell fates and functions, suggesting points at which these pathways do and do not intersect.

Regulatory T Cell Development.

Foxp3-expressing CD4+ regulatory T (Treg) cells play key roles in the prevention of autoimmunity and the maintenance of immune homeostasis and represent a major barrier to the induction of robust antitumor immune responses. Thus, a clear understanding of the mechanisms coordinating Treg cell differentiation is crucial for understanding numerous facets of health and disease and for developing approaches to modulate Treg cells for clinical benefit. Here, we discuss current knowledge of the signals that coordinate Treg cell development, the antigen-presenting cell types that direct Treg cell selection, and the nature of endogenous Treg cell ligands, focusing on evidence from studies in mice. We also highlight recent advances in this area and identify key unanswered questions.

Finding a Way Out: S1P Signaling and Immune Cell Migration.

The signaling lipid sphingosine 1-phosphate (S1P) plays critical roles in an immune response. Drugs targeting S1P signaling have been remarkably successful in treatment of multiple sclerosis, and they have shown promise in clinical trials for colitis and psoriasis. One mechanism of these drugs is to block lymphocyte exit from lymph nodes, where lymphocytes are initially activated, into circulation, from which lymphocytes can reach sites of inflammation. Indeed, S1P can be considered a circulation marker, signaling to immune cells to help them find blood and lymphatic vessels, and to endothelial cells to stabilize the vasculature. That said, S1P plays pleiotropic roles in the immune response, and it will be important to build an integrated view of how S1P shapes inflammation. S1P can function so effectively because its distribution is exquisitely tightly controlled. Here we review how S1P gradients regulate immune cell exit from tissues, with particular attention to key outstanding questions in the field.

Neonatal T Cells: A Reinterpretation.

Neonatal CD4+ and CD8+ T cells have historically been characterized as immature or defective. However, recent studies prompt a reinterpretation of the functions of neonatal T cells. Rather than a population of cells always falling short of expectations set by their adult counterparts, neonatal T cells are gaining recognition as a distinct population of lymphocytes well suited for the rapidly changing environment in early life. In this review, I will highlight new evidence indicating that neonatal T cells are not inert or less potent versions of adult T cells but instead are a broadly reactive layer of T cells poised to quickly develop into regulatory or effector cells, depending on the needs of the host. In this way, neonatal T cells are well adapted to provide fast-acting immune protection against foreign pathogens, while also sustaining tolerance to self-antigens.

Regulatory T Cells and Human Disease.

Naturally occurring CD4+ regulatory T cells (Tregs), which specifically express the transcription factor FoxP3 in the nucleus and CD25 and CTLA-4 on the cell surface, are a functionally distinct T cell subpopulation actively engaged in the maintenance of immunological self-tolerance and homeostasis. Recent studies have facilitated our understanding of the cellular and molecular basis of their generation, function, phenotypic and functional stability, and adaptability. It is under investigation in humans how functional or numerical Treg anomalies, whether genetically determined or environmentally induced, contribute to immunological diseases such as autoimmune diseases. Also being addressed is how Tregs can be targeted to control physiological and pathological immune responses, for example, by depleting them to enhance tumor immunity or by expanding them to treat immunological diseases. This review discusses our current understanding of Treg immunobiology in normal and disease states, with a perspective on the realization of Treg-targeting therapies in the clinic.

Age-Associated B Cells.

The age-associated B cell subset has been the focus of increasing interest over the last decade. These cells have a unique cell surface phenotype and transcriptional signature, and they rely on TLR7 or TLR9 signals in the context of Th1 cytokines for their formation and activation. Most are antigen-experienced memory B cells that arise during responses to microbial infections and are key to pathogen clearance and control. Their increasing prevalence with age contributes to several well-established features of immunosenescence, including reduced B cell genesis and damped immune responses. In addition, they are elevated in autoimmune and autoinflammatory diseases, and in these settings they are enriched for characteristic autoantibody specificities. Together, these features identify age-associated B cells as a subset with pivotal roles in immunological health, disease, and aging. Accordingly, a detailed understanding of their origins, functions, and physiology should make them tractable translational targets in each of these settings.

In Vivo CD4+ T Cell Differentiation and Function: Revisiting the Th1/Th2 Paradigm.

The discovery of CD4+ T cell subset-defining master transcription factors and framing of the Th1/Th2 paradigm ignited the CD4+ T cell field. Advances in in vivo experimental systems, however, have revealed that more complex lineage-defining transcriptional networks direct CD4+ T cell differentiation in the lymphoid organs and tissues. This review focuses on the layers of fate decisions that inform CD4+ T cell differentiation in vivo. Cytokine production by antigen-presenting cells and other innate cells influences the CD4+ T cell effector program [e.g., T helper type 1 (Th1), Th2, Th17]. Signals downstream of the T cell receptor influence whether individual clones bearing hallmarks of this effector program become T follicular helper cells, supporting development of B cells expressing specific antibody isotypes, or T effector cells, which activate microbicidal innate cells in tissues. These bifurcated, parallel axes allow CD4+ T cells to augment their particular effector program and prevent disease.

Antigen Receptor Function in the Context of the Nanoscale Organization of the B Cell Membrane.

The B cell antigen receptor (BCR) plays a central role in the self/nonself selection of B lymphocytes and in their activation by cognate antigen during the clonal selection process. It was long thought that most cell surface receptors, including the BCR, were freely diffusing and randomly distributed. Since the advent of superresolution techniques, it has become clear that the plasma membrane is compartmentalized and highly organized at the nanometer scale. Hence, a complete understanding of the precise conformation and activation mechanism of the BCR must take into account the organization of the B cell plasma membrane. We review here the recent literature on the nanoscale organization of the lymphocyte membrane and discuss how this new information influences our view of the conformational changes that the BCR undergoes during activation.

New Molecular Insights into Immune Cell Development.

During development innate lymphoid cells and specialized lymphocyte subsets colonize peripheral tissues, where they contribute to organogenesis and later constitute the first line of protection while maintaining tissue homeostasis. A few of these subsets are produced only during embryonic development and remain in the tissues throughout life. They are generated through a unique developmental program initiated in lympho-myeloid-primed progenitors, which lose myeloid and B cell potential. They either differentiate into innate lymphoid cells or migrate to the thymus to give rise to embryonic T cell receptor-invariant T cells. At later developmental stages, adaptive T lymphocytes are derived from lympho-myeloid progenitors that colonize the thymus, while lymphoid progenitors become specialized in the production of B cells. This sequence of events highlights the requirement for stratification in the establishment of immune functions that determine efficient seeding of peripheral tissues by a limited number of cells.

Using T Cell Receptor Repertoires to Understand the Principles of Adaptive Immune Recognition.

Adaptive immune recognition is mediated by antigen receptors on B and T cells generated by somatic recombination during lineage development. The high level of diversity resulting from this process posed technical limitations that previously limited the comprehensive analysis of adaptive immune recognition. Advances over the last ten years have produced data and approaches allowing insights into how T cells develop, evolutionary signatures of recombination and selection, and the features of T cell receptors that mediate epitope-specific binding and T cell activation. The size and complexity of these data have necessitated the generation of novel computational and analytical approaches, which are transforming how T cell immunology is conducted. Here we review the development and application of novel biological, theoretical, and computational methods for understanding T cell recognition and discuss the potential for improved models of receptor:antigen interactions.

Origin, Organization, Dynamics, and Function of Actin and Actomyosin Networks at the T Cell Immunological Synapse.

The engagement of a T cell with an antigen-presenting cell (APC) or activating surface results in the formation within the T cell of several distinct actin and actomyosin networks. These networks reside largely within a narrow zone immediately under the T cell's plasma membrane at its site of contact with the APC or activating surface, i.e., at the immunological synapse. Here we review the origin, organization, dynamics, and function of these synapse-associated actin and actomyosin networks. Importantly, recent insights into the nature of these actin-based cytoskeletal structures were made possible in several cases by advances in light microscopy.

Cancer Neoantigens.

Malignant transformation of cells depends on accumulation of DNA damage. Over the past years we have learned that the T cell-based immune system frequently responds to the neoantigens that arise as a consequence of this DNA damage. Furthermore, recognition of neoantigens appears an important driver of the clinical activity of both T cell checkpoint blockade and adoptive T cell therapy as cancer immunotherapies. Here we review the evidence for the relevance of cancer neoantigens in tumor control and the biological properties of these antigens. We discuss recent technological advances utilized to identify neoantigens, and the T cells that recognize them, in individual patients. Finally, we discuss strategies that can be employed to exploit cancer neoantigens in clinical interventions.

Self-Reactive B Cells in the Germinal Center Reaction.

Maintenance of immunological self-tolerance requires lymphocytes carrying self-reactive antigen receptors to be selectively prevented from mounting destructive or inflammatory effector responses. Classically, self-tolerance is viewed in terms of the removal, editing, or silencing of B and T cells that have formed self-reactive antigen receptors during their early development. However, B cells activated by foreign antigen can enter germinal centers (GCs), where they further modify their antigen receptor by somatic hypermutation (SHM) of their immunoglobulin genes. The inevitable emergence of activated, self-reactive GC B cells presents a unique challenge to the maintenance of self-tolerance that must be rapidly countered to avoid autoantibody production. Here we discuss current knowledge of the mechanisms that enforce B cell self-tolerance, with particular focus on the control of self-reactive GC B cells. We also consider how self-reactive GC B cells can escape self-tolerance to initiate autoantibody production or instead be redeemed via SHM and used in productive antibody responses.

ZAP-70 in Signaling, Biology, and Disease.

T cells possess an array of functional capabilities important for host defense against pathogens and tumors. T cell effector functions require the T cell antigen receptor (TCR). The TCR has no intrinsic enzymatic activity, and thus signal transduction from the receptor relies on additional signaling molecules. One such molecule is the cytoplasmic tyrosine kinase ZAP-70, which associates with the TCR complex and is required for initiating the canonical biochemical signal pathways downstream of the TCR. In this article, we describe recent structure-based insights into the regulation and substrate specificity of ZAP-70, and then we review novel methods for determining the role of ZAP-70 catalytic activity-dependent and -independent signals in developing and mature T cells. Lastly, we discuss the disease states in mouse models and humans, which range from immunodeficiency to autoimmunity, that are caused by mutations in ZAP-70.

Multidomain Control Over TEC Kinase Activation State Tunes the T Cell Response.

Signaling through the T cell antigen receptor (TCR) activates a series of tyrosine kinases. Directly associated with the TCR, the SRC family kinase LCK and the SYK family kinase ZAP-70 are essential for all downstream responses to TCR stimulation. In contrast, the TEC family kinase ITK is not an obligate component of the TCR cascade. Instead, ITK functions as a tuning dial, to translate variations in TCR signal strength into differential programs of gene expression. Recent insights into TEC kinase structure have provided a view into the molecular mechanisms that generate different states of kinase activation. In resting lymphocytes, TEC kinases are autoinhibited, and multiple interactions between the regulatory and kinase domains maintain low activity. Following TCR stimulation, newly generated signaling modules compete with the autoinhibited core and shift the conformational ensemble to the fully active kinase. This multidomain control over kinase activation state provides a structural mechanism to account for ITK's ability to tune the TCR signal.

Unraveling the Complex Interplay Between T Cell Metabolism and Function.

Metabolism drives function, on both an organismal and a cellular level. In T cell biology, metabolic remodeling is intrinsically linked to cellular development, activation, function, differentiation, and survival. After naive T cells are activated, increased demands for metabolic currency in the form of ATP, as well as biomass for cell growth, proliferation, and the production of effector molecules, are met by rewiring cellular metabolism. Consequently, pharmacological strategies are being developed to perturb or enhance selective metabolic processes that are skewed in immune-related pathologies. Here we review the most recent advances describing the metabolic changes that occur during the T cell lifecycle. We discuss how T cell metabolism can have profound effects on health and disease and where it might be a promising target to treat a variety of pathologies.

Signaling and Function of Interleukin-2 in T Lymphocytes.

The discovery of interleukin-2 (IL-2) changed the molecular understanding of how the immune system is controlled. IL-2 is a pleiotropic cytokine, and dissecting the signaling pathways that allow IL-2 to control the differentiation and homeostasis of both pro- and anti-inflammatory T cells is fundamental to determining the molecular details of immune regulation. The IL-2 receptor couples to JAK tyrosine kinases and activates the STAT5 transcription factors. However, IL-2 does much more than control transcriptional programs; it is a key regulator of T cell metabolic programs. The development of global phosphoproteomic approaches has expanded the understanding of IL-2 signaling further, revealing the diversity of phosphoproteins that may be influenced by IL-2 in T cells. However, it is increasingly clear that within each T cell subset, IL-2 will signal within a framework of other signal transduction networks that together will shape the transcriptional and metabolic programs that determine T cell fate.

Memory B Cells of Mice and Humans.

We comprehensively review memory B cells (MBCs), covering the definition of MBCs and their identities and subsets, how MBCs are generated, where they are localized, how they are maintained, and how they are reactivated. Whereas naive B cells adopt multiple fates upon stimulation, MBCs are more restricted in their responses. Evolving work reveals that the MBC compartment in mice and humans consists of distinct subpopulations with differing effector functions. We discuss the various approaches to define subsets and subset-specific roles. A major theme is the need to both deliver faster effector function upon reexposure and readapt to antigenically variant pathogens while avoiding burnout, which would be the result if all MBCs generated only terminal effector function. We discuss cell-intrinsic differences in gene expression and signaling that underlie differences in function between MBCs and naive B cells and among MBC subsets and how this leads to memory responses.