Understanding which arms of the immune response are responsible for protection against SARS-CoV-2 infection is key to predicting long-term immunity and to inform vaccine design. Two studies in this ...issue of Cell collectively suggest that, although SARS-CoV-2 infection may blunt long-lived antibody responses, immune memory might still be achieved through virus-specific memory T cells.
Understanding which arms of the immune response are responsible for protection against SARS-CoV-2 infection is key to predicting long-term immunity and to inform vaccine design. Two studies in this issue of Cell collectively suggest that, although SARS-CoV-2 infection may blunt long-lived antibody responses, immune memory might still be achieved through virus-specific memory T cells.
Abstract
Vaccination stands as the cornerstone in the battle against infectious diseases, and its efficacy hinges on several host-related factors like genetics, age, and metabolic status. Vulnerable ...populations, such as malnourished individuals, the obese, and the elderly, commonly exhibit diminished vaccine responses and efficacy. While the specific factors contributing to this impairment may vary, these individuals typically display a degree of metabolic dysregulation, thereby underscoring its potential significance as a fundamental determinant of suboptimal vaccine responses. The emerging field of immunometabolism aims to unravel the intricate interplay between immune regulation and metabolic pathways, and recent research has revealed diverse metabolic signatures linked to various vaccine responses and outcomes. In this review, we summarize the major metabolic pathways utilized by B and T cells during vaccine responses, their complex and varied metabolic requirements, and the impact of micronutrients and metabolic hormones on vaccine outcomes. Furthermore, we examine how systemic metabolism influences vaccine responses and the evidence suggesting that metabolic dysregulation in vulnerable populations can lead to impaired vaccine responses. Lastly, we reflect on the challenge of proving causality with respect to the contribution of metabolic dysregulation to poor vaccine outcomes, and highlight the need for a systems biology approach that combines multimodal profiling and mathematical modelling to reveal the underlying mechanisms of such complex interactions.
Graphical Abstract
Graphical Abstract
Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease
, evidence of lupus-causing TLR7 gene variants is ...lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA
,
and binds to guanosine
-
. We identified a de novo, previously undescribed missense TLR7
variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7
variant selectively increased sensing of guanosine and 2',3'-cGMP
, and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c
age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7
mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.
T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. ...Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3
regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation.
Mucosal lymphoid tissues such as human tonsil are colonized by bacteria and exposed to ingested and inhaled antigens, requiring tight regulation of immune responses. Antibody responses are regulated ...by follicular helper T (T
) cells and FOXP3
follicular regulatory T (T
) cells. Here we describe a subset of human tonsillar follicular T cells identified by expression of T
markers and CD25 that are the main source of follicular T (T
) cell-derived IL-10. Despite lack of FOXP3 expression, CD25
T
cells resemble T reg cells in high CTLA4 expression, low IL-2 production, and their ability to repress T cell proliferation. CD25
T
cell-derived IL-10 dampens induction of B cell class-switching to IgE. In children, circulating total IgE titers were inversely correlated with the frequencies of tonsil CD25
T
cells and IL-10-producing T
cells but not with total T reg cells, T
, or IL-10-producing T cells. Thus, CD25
T
cells emerge as a subset with unique T and B cell regulatory activities that may help prevent atopy.
Class-switch recombination (CSR) is a DNA recombination process that replaces the immunoglobulin (Ig) constant region for the isotype that can best protect against the pathogen. Dysregulation of CSR ...can cause self-reactive BCRs and B cell lymphomas; understanding the timing and location of CSR is therefore important. Although CSR commences upon T cell priming, it is generally considered a hallmark of germinal centers (GCs). Here, we have used multiple approaches to show that CSR is triggered prior to differentiation into GC B cells or plasmablasts and is greatly diminished in GCs. Despite finding a small percentage of GC B cells expressing germline transcripts, phylogenetic trees of GC BCRs from secondary lymphoid organs revealed that the vast majority of CSR events occurred prior to the onset of somatic hypermutation. As such, we have demonstrated the existence of IgM-dominated GCs, which are unlikely to occur under the assumption of ongoing switching.
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•Germline transcripts peak prior to GC formation and rapidly decline in GCs•IgM-dominated clones are found in late GCs, arguing against ongoing Ig switching•CSR largely ceases upon the onset of somatic hypermutation•CSR decline due to low GLT and APE1 expression is possibly orchestrated by BCL6
Germinal centers (GCs) have long been considered sites in which Ig class-switch recombination (CSR) is favored. Roco et al. show that CSR occurs during the initial T cell:B cell interaction prior to GC formation and rapidly declines as B cells differentiate into GC cells and somatic hypermutation commences.
The common γ chain family of cytokines and their receptors play fundamental roles in the immune system. Evolutionary studies of γ chain cytokines have elegantly illustrated how the immune system ...adapts to ever-changing environmental conditions. Indeed, these studies have revealed the uniqueness of cytokine evolution, which exhibits strong positive selection pressure needed to adapt to rapidly evolving threats whilst still conserving their receptor binding capabilities. In this review, we summarise the evolutionary mechanisms that gave rise to the characteristically diverse family of γ chain cytokines. We also speculate on the benefits of studying cytokine evolution, which may provide alternative ways to design novel cytokine therapeutic strategies. Additionally, we discuss current evolutionary models that elucidate the emergence of distinct cytokines (IL-4 and IL-13) and cytokine receptors (IL-2Rα and IL-15Rα). Finally, we address and reflect on the difficulties associated with evolutionary studies of rapidly evolving genes and describe a variety of computational methods that have revealed numerous aspects of cytokine evolution.
Regulatory T cells prevent the emergence of autoantibodies and excessive IgE, but the precise mechanisms are unclear. Here, we show that BCL6-expressing Tregs, known as follicular regulatory T (Tfr) ...cells, produce abundant neuritin protein that targets B cells. Mice lacking Tfr cells or neuritin in Foxp3-expressing cells accumulated early plasma cells in germinal centers (GCs) and developed autoantibodies against histones and tissue-specific self-antigens. Upon immunization, these mice also produced increased plasma IgE and IgG1. We show that neuritin is taken up by B cells, causes phosphorylation of numerous proteins, and dampens IgE class switching. Neuritin reduced differentiation of mouse and human GC B cells into plasma cells, downregulated BLIMP-1, and upregulated BCL6. Administration of neuritin to Tfr-deficient mice prevented the accumulation of early plasma cells in GCs. Production of neuritin by Tfr cells emerges as a central mechanism to suppress B cell-driven autoimmunity and IgE-mediated allergies.
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•Tfr cells control the emergence of aberrant CD138+ germinal center B cells•Neuritin-deficiency in Foxp3+ cells leads to spontaneous autoantibody production•Neuritin limits IgE class switch recombination•Exogenous neuritin suppresses conventional and aberrant plasma cell differentiation
Follicular regulatory T cells produce an abundance of neuritin protein, which acts directly on B cells to suppress B cell-driven autoimmunity and IgE-mediated allergies.
In antibody responses, mutated germinal center B (B
) cells are positively selected for reentry or differentiation. As the products from GCs, memory B cells and antibody-secreting cells (ASCs) ...support high-affinity and long-lasting immunity. Positive selection of B
cells is controlled by signals received through the B cell receptor (BCR) and follicular helper T (T
) cell-derived signals, in particular costimulation through CD40. Here, we demonstrate that the T
cell effector cytokine interleukin-21 (IL-21) joins BCR and CD40 in supporting B
selection and reveal that strong IL-21 signaling prioritizes ASC differentiation in vivo. B
cells, compared with non-B
cells, show significantly reduced IL-21 binding and attenuated signaling, which is mediated by low cellular heparan sulfate (HS) sulfation. Mechanistically, N-deacetylase and N-sulfotransferase 1 (Ndst1)-mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength. Ndst1 is down-regulated in B
cells and up-regulated in ASC precursors, suggesting selective desensitization to IL-21 in B
cells. Thus, specialized biochemical regulation of IL-21 bioavailability and signal strength sets a balance between the stringency and efficiency of GC selection.
As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody deficiency (PAD), analysis of affected patients could yield insights into T-cell differentiation and ...explain how environmental exposures modify clinical phenotypes conferred by single-gene defects. CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation. Indeed, while circulating CD57
CD4
T cells are normally rare, we found that they are increased in patients with PAD and markedly increased with CTLA4 haploinsufficiency or blockade. We performed single-cell RNA-seq analysis of matched CD57
CD4
T cells from blood and tonsil samples. Circulating CD57
CD4
T cells (CD4cyt) exhibited a cytotoxic transcriptome similar to that of CD8
effector cells, could kill B cells, and inhibited B-cell responses. CTLA4 restrained the formation of CD4cyt. While CD57 also marked an abundant subset of follicular helper T cells, which is consistent with their antigen-driven differentiation, this subset had a pre-exhaustion transcriptomic signature marked by TCF7, TOX, and ID3 expression and constitutive expression of CTLA4 and did not become cytotoxic even after CTLA4 inhibition. Thus, CD57
CD4
T-cell cytotoxicity and exhaustion phenotypes are compartmentalised between blood and germinal centers. CTLA4 is a key modifier of CD4
T-cell cytotoxicity, and the pathological CD4cyt phenotype is accentuated by infection.
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