Inborn errors of immunity (IEI) are caused by monogenic variants that affect the host response to bacterial, viral, and fungal pathogens. As such, individuals with IEI often present with severe, ...recurrent, and life-threatening infections. However, the spectrum of disease due to IEI is very broad and extends to include autoimmunity, malignancy, and atopic diseases such as eczema, atopic dermatitis, and food and environmental allergies. Here, I review IEI that affect cytokine signaling pathways that dysregulate CD4+ T-cell differentiation, resulting in increased T-helper-2 (Th2) cell development, function, and pathogenicity. These are elegant examples of how rare IEI can provide unique insights into more common pathologies such as allergic disease that are impacting the general population at increased frequency.
•Interleukin (IL)-6/STAT3/ERBIN pathway retrains human Th2 cells.•IFNγ, but not IL-12, is a negative regulator of human Th2 cell development.•STAT6 is a key driver of Th2 cells and atopic disease.
Cytokines play critical roles in regulating the development, survival, differentiation, and function of immune cells. Cytokines exert their function by binding specific receptor complexes on the ...surface of immune cells and activating intracellular signaling pathways, thereby resulting in induction of specific transcription factors and regulated expression of target genes. While the function of cytokines is often fundamental for the generation of robust and effective immunity following infection or vaccination, aberrant production or function of cytokines can underpin immunopathology. IL-21 is a pleiotropic cytokine produced predominantly by CD4+ T cells. Gene-targeting studies in mice, in vitro analyses of human and murine lymphocytes, and the recent discoveries and analyses of humans with germline loss-of-function mutations in IL21 or IL21R have revealed diverse roles of IL-21 in immune regulation and effector function. This review will focus on recent advances in IL-21 biology that have highlighted its critical role in T cell-dependent B cell activation, germinal center reactions, and humoral immunity and how impaired responses to, or production of, IL-21 can lead to immune dysregulation.
Antibody production is an important feature of the vertebrate immune system. Antibodies neutralize and clear pathogens, thereby protecting against infectious diseases. Such humoral immunity has great ...longevity, often persisting for the host's lifetime. Long-lived humoral immunity depends on help provided by CD4(+) T cells, namely T follicular helper (TFH) cells, which support the differentiation of antigen-specific B cells into memory and plasma cells. TFH cells are stringently regulated, as aberrant TFH cell activity is involved in immunopathologies such as autoimmunity, immunodeficiencies and lymphomas. The elucidation of the mechanisms that regulate TFH cell differentiation, function and fate should highlight targets for novel therapeutics.
This article examines the discourse of “alt-lite” YouTube personalities in a North American context, with a focus on how whiteness is understood and represented. It argues that, despite their ...self-presentation as color-blind conservatives, these figures are firmly embedded within white supremacist ideology. A qualitative approach to content analysis is adopted to excavate the logics underlying these videos and to highlight the rhetorical tools at work. By framing themselves as the vulnerable targets of progressive movements, “alt-lite” personalities have helped to revive and legitimize a discourse of white victimhood. Their videos emphasize the historic dominance of “white culture” while bemoaning the current and future vulnerability of white people in a politically correct, social-justice-oriented world. Ultimately, the article argues that “alt-lite” figures are united by a set of mitigating rhetorical strategies, which are used to temper and obfuscate their reactionary views. These strategies include performatively aligning with one minority group to denigrate another; highlighting personal relationships with non-white people and knowledge of non-white cultures; embracing a color-blind worldview purportedly rooted in the civil rights movement; and maintaining ironic distance when espousing more overtly hateful racial stereotypes. The adoption of these strategies by right-wing micro-celebrities should not deter scholars and civil society groups from acknowledging when those same figures traffic in white supremacist rhetoric.
The generation of high-affinity antibodies (Abs) plays a critical role in the neutralization and clearance of pathogens and subsequent host survival after natural infection with a variety of ...microorganisms. Most currently available vaccines rely on the induction of long-lived protective humoral immune responses by memory B cells and plasma cells, underscoring the importance of Abs in host protection. Ab responses against most antigens (Ags) require interactions between B cells and CD4(+) T helper cells, and it is now well recognized that T follicular helper cells (Tfh) specialize in providing cognate help to B cells and are fundamentally required for the generation of T cell-dependent B cell responses. Perturbations in the development and/or function of Tfh cells can manifest as immunopathologies, such as immunodeficiency, autoimmunity, and malignancy. Unraveling the cellular and molecular requirements underlying Tfh cell formation and maintenance will help to identify molecules that could be targeted for the treatment of immunological diseases that are characterized by insufficient or excessive Ab responses.
T follicular helper (Tfh) cells cognately guide differentiation of antigen-primed B cells in secondary lymphoid tissues. ‘Tfh-like’ populations not expressing the canonical Tfh cell transcription ...factor BCL6 have also been described, which can aid particular aspects of B cell differentiation. Tfh and Tfh-like cells are essential for protective and pathological humoral immunity. These CD4+ T cells that help B cells are polarized to produce diverse combinations of cytokines and chemokine receptors and can be grouped into distinct subsets that promote antibodies of different isotype, affinity, and duration, according to the nature of immune challenge. However, unified nomenclature to describe the distinct functional Tfh and Tfh-like cells does not exist. While explicitly acknowledging cellular plasticity, we propose categorizing these cell states into three groups based on phenotype and function, paired with their anatomical site of action.
We propose a group 1, 2, and 3 classification system for CD4+ T cells that help B cells based on differential expression of signature cytokines, transcription factors, and chemokine receptors, paralleling nomenclatures used for other lymphoid subsets.This nomenclature is applicable to BCL6-dependent T follicular helper (Tfh) cells but also BCL6-independent Tfh-like cells that specifically help B cells and are functional in a variety of anatomical sites.These three groups of Tfh/Tfh-like cells induce distinct types of B cell responses.This concept does not exclude cellular plasticity, either between the three groups or between Tfh cells and other effector CD4+ T cell types.
Follicular B helper T (Tfh) cells support high affinity and long-term antibody responses. Here we found that within circulating CXCR5+ CD4+ T cells in humans and mice, the CCR7loPD-1hi subset has a ...partial Tfh effector phenotype, whereas CCR7hiPD-1lo cells have a resting phenotype. The circulating CCR7loPD-1hi subset was indicative of active Tfh differentiation in lymphoid organs and correlated with clinical indices in autoimmune diseases. Thus the CCR7loPD-1hi subset provides a biomarker to monitor protective antibody responses during infection or vaccination and pathogenic antibody responses in autoimmune diseases. Differentiation of both CCR7hiPD-1lo and CCR7loPD-1hi subsets required ICOS and BCL6, but not SAP, suggesting that circulating CXCR5+ helper T cells are primarily generated before germinal centers. Upon antigen reencounter, CCR7loPD-1hi CXCR5+ precursors rapidly differentiate into mature Tfh cells to promote antibody responses. Therefore, circulating CCR7loPD-1hi CXCR5+ CD4+ T cells are generated during active Tfh differentiation and represent a new mechanism of immunological early memory.
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•Circulating CXCR5+ CD4+ T cells comprise CCR7loPD-1hi and CCR7hiPD-1lo subsets•Circulating CXCR5+ CD4+ T cells are primarily generated before participating in GC•Circulating CCR7loPD-1hi CXCR5+ CD4+ T cells correlate with Tfh cell activity•Circulating CCR7loPD-1hi CXCR5+ CD4+ T cells promote antibody responses
The generation of protective antibodies by B cells following natural infection or vaccination requires 'help' from CD4(+) T cells. T follicular helper (Tfh) cells are the specialized CD4(+) T cell ...subset that has evolved the appropriate mechanisms to induce the activation and differentiation of B cells into immunoglobulin (Ig) secreting cells. As such, appropriate control of Tfh cell generation and function is essential to human health as overactivation is likely to result in autoimmunity, whereas underactivation is often associated with immunodeficiency. Furthermore, an understanding of the regulation of these cells may be invaluable to improved vaccine development strategies. Traditionally Tfh cells have been identified by their anatomical location in secondary lymphoid tissues, which has hindered the study of these cells in humans as access to these tissues is often not feasible. However, recent studies have identified the circulating counterparts to tissue Tfh cells and with this has come a wealth of knowledge gained from the study of these cells in human disease. Here we review some of the recent developments on the role of human Tfh cells in health and disease.
Summary
The STAT3 story has almost 30 years of evolving history. First identified in 1994 as a pro-inflammatory transcription factor, Signal Transducer and Activator of Transcription 3 (STAT3) has ...continued to be revealed as a quintessential pleiotropic signalling module spanning fields including infectious diseases, autoimmunity, vaccine responses, metabolism, and malignancy. In 2007, germline heterozygous dominant-negative loss-of-function variants in STAT3 were discovered as the most common cause for a triad of eczematoid dermatitis with recurrent skin and pulmonary infections, first described in 1966. This finding established that STAT3 plays a critical non-redundant role in immunity against some pathogens, as well as in the connective tissue, dental and musculoskeletal systems. Several years later, in 2014, heterozygous activating gain of function germline STAT3 variants were found to be causal for cases of early-onset multiorgan autoimmunity, thereby underpinning the notion that STAT3 function needed to be regulated to maintain immune homeostasis. As we and others continue to interrogate biochemical and cellular perturbations due to inborn errors in STAT3, we will review our current understanding of STAT3 function, mechanisms of disease pathogenesis, and future directions in this dynamic field.
Inborn errors of STAT3 immunity can result in diverse clinical phenotypes due to activating/gin of function or dominant negative/loss of function variants. These conditions manifest as immune dysregulation, as well as non-immune defects. Targeted therapies guided by genotype can improve patient outcomes.
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Graphical Abstract
Summary
The essential role of B cells is to produce protective immunoglobulins (Ig) that recognize, neutralize, and clear invading pathogens. This results from the integration of signals provided by ...pathogens or vaccines and the stimulatory microenvironment within sites of immune activation, such as secondary lymphoid tissues, that drive mature B cells to differentiate into memory B cells and antibody (Ab)‐secreting plasma cells. In this context, B cells undergo several molecular events including Ig class switching and somatic hypermutation that results in the production of high‐affinity Ag‐specific Abs of different classes, enabling effective pathogen neutralization and long‐lived humoral immunity. However, perturbations to these key signaling pathways underpin immune dyscrasias including immune deficiency and autoimmunity or allergy. Inborn errors of immunity that disrupt critical immune pathways have identified non‐redundant requirements for eliciting and maintaining humoral immune memory but concomitantly prevent immune dysregulation. Here, we will discuss our studies on human B cells, and how our investigation of cytokine signaling in B cells have identified fundamental requirements for memory B‐cell formation, Ab production as well as regulating Ig class switching in the context of protective versus allergic immune responses.
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