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During pregnancy, various immune effectors and molecules participating in the immune-microenvironment establish specific maternal tolerance toward the semi-allogeneic fetus. Activated maternal immune effectors by the trophoblast antigens, such as T helper (Th), T cytotoxic (Tc), T regulatory (Treg), and B cells, are involved in the regulation of adaptive immunity. Recognition of active signal through the T cell receptors stimulate the differentiation of naive CD3 CD4 T cells into specific T cell subsets, such as Th1, Th2, Th9, Th17, Th22, and follicular Th cells (Tfh). Each of these subsets has a significant and distinct role in human pregnancy. Th1 immunity, characterized by immune-inflammatory responses, becomes dominant during the peri-implantation period, and the \"controlled\" Th1 immunity benefits the invading trophoblasts rather than harm. Quickly after the placental implantation, the early inflammatory Th1 immunity is shifted to the Th2 anti-inflammatory immune responses. The predominant Th2 immunity, which overrules the Th1 immunity at the placental implantation site, protects a fetus by balancing Th1 immunity and accommodate fetal and placental development. Moreover, Treg and Th9 cells regulate local inflammatory immune responses, potentially detrimental to the fetus. Th17 cells induce protective immunity against extracellular microbes during pregnancy. However, excessive Th17 immunity may induce uncontrolled neutrophil infiltration at the maternal-fetal interface. Other Th cell subsets such as Tfh cells, also contribute to pregnancy by setting up favorable humoral immunity during pregnancy. However, dysregulation of Th cell immunity during pregnancy may result in obstetrical complications, such as recurrent pregnancy losses (RPL) and preeclampsia (PE). With this review, we intend to deliver a comprehensive overview of CD4 Th cell subsets, including Th1, Th2, Th9, Th17, Th22, and Tfh cells, in human pregnancy by reviewing their roles in normal and pathological pregnancies.

Follicular helper T (T FH ) cells are a specialized subset of CD4 + T cells that essentially support germinal center responses where high-affinity and long-lived humoral immunity is generated. The regulation of T FH cell survival remains unclear. Here we report that T FH cells show intensified lipid peroxidation and altered mitochondrial morphology, resembling the features of ferroptosis, a form of programmed cell death that is driven by iron-dependent accumulation of lipid peroxidation. Glutathione peroxidase 4 (GPX4) is the major lipid peroxidation scavenger and is necessary for T FH cell survival. The deletion of GPX4 in T cells selectively abrogated T FH cells and germinal center responses in immunized mice. Selenium supplementation enhanced GPX4 expression in T cells, increased T FH cell numbers and promoted antibody responses in immunized mice and young adults after influenza vaccination. Our findings reveal the central role of the selenium–GPX4–ferroptosis axis in regulating T FH homeostasis, which can be targeted to enhance T FH cell function in infection and following vaccination. T follicular helper (T FH ) cells are important for the generation of effective antibody responses. Yu and colleagues find that T FH cells are exceptionally sensitive to death by ferroptosis and that this process is regulated by the activity of the selenoenzyme GPX4.

Gastrointestinal health depends on the adaptive immune system tolerating the foreign proteins in food 1 , 2 . This tolerance is paradoxical because the immune system normally attacks foreign substances by generating inflammation. Here we addressed this conundrum by using a sensitive cell enrichment method to show that polyclonal CD4 + T cells responded to food peptides, including a natural one from gliadin, by proliferating weakly in secondary lymphoid organs of the gut–liver axis owing to the action of regulatory T cells. A few food-specific T cells then differentiated into T follicular helper cells that promoted a weak antibody response. Most cells in the expanded population, however, lacked canonical T helper lineage markers and fell into five subsets dominated by naive-like or T follicular helper-like anergic cells with limited capacity to form inflammatory T helper 1 cells. Eventually, many of the T helper lineage-negative cells became regulatory T cells themselves through an interleukin-2-dependent mechanism. Our results indicate that exposure to food antigens causes cognate CD4 + naive T cells to form a complex set of noncanonical hyporesponsive T helper cell subsets that lack the inflammatory functions needed to cause gut pathology and yet have the potential to produce regulatory T cells that may suppress it. Immune tolerance to food is mediated by CD4 + T cells forming subsets of T helper cells lacking the capacity to trigger gut pathology but able to produce regulatory T cells that may suppress it.

We previously demonstrated that tumor-infiltrating lymphocytes (TIL) in human breast cancer sometimes form organized tertiary lymphoid structures (TLS) characterized by CXCL13-producing T follicular helper (Tfh) cells. The present study found that CD4+ Tfh TIL, CD8+ TIL, and TIL-B, colocalizing in TLS, all express the CXCL13 receptor CXCR5. An ex vivo functional assay determined that only activated, functional Th1-oriented Tfh TIL (PD-1hiICOSint phenotype) provide help for immunoglobulin and IFN-γ production. A functional Tfh TIL presence signals an active TLS, characterized by humoral (immunoglobulins, Ki-67+ TIL-B in active germinal centers) and cytotoxic (GZMB+CD8+ and GZMB+CD68+ TIL plus Th1 gene expression) immune responses. Analysis of active versus inactive TLS in untreated patients revealed that the former are associated with positive clinical outcomes. TLS also contain functional T follicular regulatory (Tfr) TIL, which are characterized by a CD25+CXCR5+GARP+FOXP3+ phenotype and a demethylated FOXP3 gene. Functional Tfr inhibited functional Tfh activities via a glycoprotein A repetitions predominant (GARP)-associated TGF-β-dependent mechanism. The activity of tumor-associated TLS was dictated by the relative balance between functional Tfh TIL and functional Tfr TIL. These data provide mechanistic insight into TLS processes orchestrated by functional Th1-oriented Tfh TIL, including TIL-B and CD8+ TIL activation and immunological memory generation. Tfh TIL, regulated by functional Tfr TIL, are an expected key target of PD-1/PD-L1 blockade.

Immune cells rely on transient physical interactions with other immune and non-immune populations to regulate their function 1 . To study these ‘kiss-and-run’ interactions directly in vivo, we previously developed LIPSTIC (labelling immune partnerships by SorTagging intercellular contacts) 2 , an approach that uses enzymatic transfer of a labelled substrate between the molecular partners CD40L and CD40 to label interacting cells. Reliance on this pathway limited the use of LIPSTIC to measuring interactions between CD4 + T helper cells and antigen-presenting cells, however. Here we report the development of a universal version of LIPSTIC (uLIPSTIC), which can record physical interactions both among immune cells and between immune and non-immune populations irrespective of the receptors and ligands involved. We show that uLIPSTIC can be used, among other things, to monitor the priming of CD8 + T cells by dendritic cells, reveal the steady-state cellular partners of regulatory T cells and identify germinal centre-resident T follicular helper cells on the basis of their ability to interact cognately with germinal centre B cells. By coupling uLIPSTIC with single-cell transcriptomics, we build a catalogue of the immune populations that physically interact with intestinal epithelial cells at the steady state and profile the evolution of the interactome of lymphocytic choriomeningitis virus-specific CD8 + T cells in multiple organs following systemic infection. Thus, uLIPSTIC provides a broadly useful technology for measuring and understanding cell–cell interactions across multiple biological systems. A paper reports the development of a universal tool for studying cellular interactions in biological systems, and demonstrates its coupling with single-cell transcriptomics methods to provide insights into the biology of the interactions.

The interactions of CD4+ T cells and B cells are fundamental for the generation of protective antibody responses, as well as for the development of harmful autoimmune diseases. Recent studies of human tissues and blood samples have established a new subset of CD4+ B helper T cells named peripheral helper T (Tph) cells. Unlike T follicular helper (Tfh) cells, which interact with B cells within lymphoid organs, Tph cells provide help to B cells within inflamed tissues. Tph cells share many B helper-associated functions with Tfh cells and induce B cell differentiation toward antibody-producing cells. The differentiation mechanism is also partly shared between Tph and Tfh cells in humans, and both Tfh and Tph cells can be found within the same tissues, including cancer tissues. However, Tph cells display features distinct from those of Tfh cells, such as the expression of chemokine receptors associated with Tph cell localization within inflamed tissues and a low Bcl-6/Blimp1 ratio. Unlike that of Tfh cells, current evidence shows that the target of Tph cells is limited to memory B cells. In this review, we first summarize recent findings on human Tph cells and discuss how Tph and Tfh cells play shared and distinct roles in human diseases.

ObjectivesTo explore the relevance of T-follicular-helper (Tfh) and pathogenic peripheral-helper T-cells (Tph) in promoting ectopic lymphoid structures (ELS) and B-cell mucosa-associated lymphoid tissue (MALT) lymphomas (MALT-L) in Sjögren’s syndrome (SS) patients.MethodsSalivary gland (SG) biopsies with matched peripheral blood were collected from four centres across the European Union. Transcriptomic (microarray and quantitative PCR) analysis, FACS T-cell immunophenotyping with intracellular cytokine detection, multicolor immune-fluorescence microscopy and in situ hybridisation were performed to characterise lesional and circulating Tfh and Tph-cells. SG-organ cultures were used to investigate functionally the blockade of T-cell costimulatory pathways on key proinflammatory cytokine production.ResultsTranscriptomic analysis in SG identified Tfh-signature, interleukin-21 (IL-21) and the inducible T-cell co-stimulator (ICOS) costimulatory pathway as the most upregulated genes in ELS+SS patients, with parotid MALT-L displaying a 400-folds increase in IL-21 mRNA. Peripheral CD4+CXC-motif chemokine receptor 5 (CXCR5)+programmed cell death protein 1 (PD1)+ICOS+ Tfh-like cells were significantly expanded in ELS+SS patients, were the main producers of IL-21, and closely correlated with circulating IgG and reduced complement C4. In the SG, lesional CD4+CD45RO+ICOS+PD1+ cells selectively infiltrated ELS+ tissues and were aberrantly expanded in parotid MALT-L. In ELS+SG and MALT-L parotids, conventional CXCR5+CD4+PD1+ICOS+Foxp3- Tfh-cells and a uniquely expanded population of CXCR5-CD4+PD1hiICOS+Foxp3- Tph-cells displayed frequent IL-21/interferon-γ double-production but poor IL-17 expression. Finally, ICOS blockade in ex vivo SG-organ cultures significantly reduced the production of IL-21 and inflammatory cytokines IL-6, IL-8 and tumour necrosis factor-α (TNF-α).ConclusionsOverall, these findings highlight Tfh and Tph-cells, IL-21 and the ICOS costimulatory pathway as key pathogenic players in SS immunopathology and exploitable therapeutic targets in SS.

Sustained CD4+ T cell immunity is required for resolution of acute hepatitis C virus (HCV) infection, but the response remains poorly characterized. Here, circulating CD4+ T cells with high programmed cell death 1 (PD-1) and ICOS coexpression were temporally associated with onset of virus control, seroconversion, and hepatitis in HCV-infected chimpanzees. Coproduction of T follicular helper (Tfh) (IL-21 and CXCL13) and Th1 (IFN-γ and TNF) cytokines after stimulation with HCV nonstructural proteins demonstrated that the response was predominately Tfh1 like and virus specific. Transcriptional analysis verified a Tfh1 lineage assignment. Effector-related genes such as ADGRG1 (GPR56), ZNF683 (Hobit), and KLRB1 (CD161) were also expressed. HCV-specific PD-1hiICOShi CD4+ Tfh1-like cells were enriched in liver, suggesting the potential for B and CD8+ T cell help at the site of virus replication. Most circulating and intrahepatic PD-1hiICOShi CD4+ Tfh1-like cells did not express CXCR5 and therefore resembled CXCR5-CXCL13+ peripheral helper cells that infiltrate tumors and tissues inflamed by autoimmunity. PD-1hiICOShi CD4+ Tfh1-like cells also peaked after hepatitis A virus infection, but the response was accelerated by several weeks compared with HCV infection. The PD-1hiICOShi phenotype and temporal association between the peak response and alanine aminotransferase may provide markers to guide human studies of CD4+ T cell immunity against HCV and other hepatotropic viruses.

Recent technological progress has greatly advanced our understanding of human immunology. In particular, the discovery of human T follicular helper (Tfh) and T peripheral helper (Tph) cells has significantly advanced our understanding of human adaptive immune system. Tfh and Tph cells share similar molecular characteristics and both play critical roles in B cell differentiation and maturation. However, they differ in their functional properties, such as chemokine receptor expression and cytokine production. As a result, Tfh cells are mainly involved in B cell differentiation and maturation in germinal centres of secondary lymphoid tissues, while Tph cells are involved in B cell differentiation and tissue damage in peripheral inflammatory lesions. Importantly, the involvement of Tfh and Tph cells in the pathogenesis of rheumatic and musculoskeletal diseases has become clear. In rheumatoid arthritis and systemic lupus erythematosus, Tph cell infiltration is predominant in peripheral inflammatory lesions, whereas Tfh cell infiltration is predominant in the affected lesions of IgG4-related disease. Therefore, the contribution of Tfh and Tph cells to the development of rheumatic and musculoskeletal diseases varies depending on each disease. In this review, we provide an overview of human Tfh and Tph cells and summarise the latest findings on these novel T cell subsets in various rheumatic and musculoskeletal diseases.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by anti-nuclear autoantibodies whose production is promoted by autoreactive T follicular helper (TFH) cells. During SLE pathogenesis, basophils accumulate in secondary lymphoid organs (SLO), amplify autoantibody production and disease progression through mechanisms that remain to be defined. Here, we provide evidence for a direct functional relationship between TFH cells and basophils during lupus pathogenesis, both in humans and mice. PD-L1 upregulation on basophils and IL-4 production are associated with TFH and TFH2 cell expansions and with disease activity. Pathogenic TFH cell accumulation, maintenance, and function in SLO were dependent on PD-L1 and IL-4 in basophils, which induced a transcriptional program allowing TFH2 cell differentiation and function. Our study establishes a direct mechanistic link between basophils and TFH cells in SLE that promotes autoantibody production and lupus nephritis. Basophils have been implicated in systemic lupus erythematosus (SLE), as evidenced by the fact that basophil-deficient mice do not develop the disease. Here, the authors demonstrate that PD-L1 and IL-4 expression in basophils promotes the pathogenic accumulation of follicular helper T cells in patients with SLE and murine models.