Explore the vast range of titles available.

To determine whether baseline CD4+ T helper (Th) cell subset proportions in blood may serve as predictive biomarkers for achieving remission 48 weeks after initiating CTLA-4Ig, anti-tumor necrosis factor (TNF), or anti-interleukin 6 receptor (IL6R) treatment in patients with early rheumatoid arthritis (eRA). This study included 60 untreated eRA patients from the larger randomized treatment trial NORD-STAR. They were treated with methotrexate (MTX) combined with either CTLA-4Ig (n = 17), anti-TNF (n = 22), or anti-IL6R (n = 21). Disease activity was assessed by clinical disease activity index (CDAI), C-reactive protein, and erythrocyte sedimentation rate. The primary outcome was remission (CDAI ≤ 2.8) at week 48, and the secondary outcomes were time to reach remission or sustained remission during the 48-week follow-up. CD4+ T cell subset proportions were analyzed fresh by flow cytometry at baseline and at 24 and 48 weeks. In CTLA-4Ig + MTX-treated patients, baseline Th2 together with PD1+ T follicular helper (TFh) cell proportions predicted CDAI remission at week 48 (AUC: 0.986, 95% CI 0.94-1.0). Survival analysis revealed that patients with Th2 proportions below 16.8% or PD1+ TFh proportions above 7.6% at baseline were more likely to achieve remission (log-rank p = 0.002 and p = 0.007, respectively), and sustained remission (log-rank p = 0.01 and p = 0.001, respectively), over the 48-week follow-up. CD4+ T cell subset proportions did not predict remission in patients treated with anti-TNF + MTX or anti-IL6R + MTX. Only CTLA-4Ig treatment reduced PD1+ TFh and PD1neg TFh fractions after 48 weeks. Circulating Th2 and PD1+ TFh cell proportions at baseline may serve as predictive biomarkers for achieving CDAI remission after 48 weeks of CTLA-4Ig treatment in eRA.

Nodal marginal zone lymphoma (NMZL) is an indolent B-cell lymphoma that may pose diagnostic challenges due to the absence of distinct markers. In rare atypical cases, an overabundance of PD1+ T follicular helper (TFH) cells in tumor tissue may mimic peripheral T-cell lymphoma (PTCL) of TFH origin, further complicating the diagnosis. A 72-year-old woman with progressive lymphadenopathy had a cervical lymph node biopsy showing a disrupted architecture with monomorphic nodules of CD20+/MNDA+ B-cells and a prominent central population of proliferating CD4+/PD1+ T-cells, initially suggestive of a PTCL-TFH. The bone marrow contained aggregates of CD20+ B-cells intermixed with CD3+/CD4+/PD1+ T-cells. Next-generation sequencing (NGS) revealed clonal immunoglobulin heavy-chain rearrangements in the lymph node and bone marrow, with T-cell receptor genes displaying a polyclonal pattern. Targeted NGS showed no PTCL-related alterations but identified NMZL-associated mutations with different distributions across lymph node and bone marrow compartments. NOTCH2 mutations (c.6418C>T; p.Gln2140*) were found in both tissues, while the (c.69+2T>A; p.?) TNFRSF14 gene mutation was only detected in the lymph node. The KMT2D gene displayed a frameshift variant in the lymph node (c.4801_4802delinsT; p.Arg1601Leufs*3) and an in-frame deletion (c.11756_11758del; p.Gln3919del) in the bone marrow. Notably, NGS and digital droplet PCR confirmed a TP53 frameshift mutation (c.902del; p.Pro301Glnfs*44) with a fractional abundance of 0.31% in the lymph node and a (c.742C>T; p.Arg248Trp) mutation (0.309%) in the bone marrow. Results underscore the importance of NGS-based clonality to diagnose NMZL with prominent PD1+ T-cell hyperplasia, and prompt further investigation into tissue-specific mutational signatures in these unusual cases.

Identifying signaling pathways that induce B cell response can aid functional cure strategies for chronic hepatitis B infection (CHB). TLR8 activation with ssRNA was shown to enhance follicular helper T cell (T FH ) function leading to improved B cell responses in vitro . We investigated whether this mechanism can rescue an exhausted immune response in CHB infection. Effect of TLR8 agonism on supporting cytokines and T FH and B cells were evaluated using ex vivo and in vitro assays. The ability of an oral TLR8 agonist to promote T FH and B cell response was tested in samples from phase 1b clinical trial. TLR8 agonism induced T FH polarizing cytokine IL-12 in monocytes. Treatment of peripheral blood mononuclear cells (PBMCs) from CHB patients with TLR8 agonists induced cytokine IL-21 by T FH cells with enhanced IL-21 + BCL-6 + and ICOS + BCL-6 + co-expression. Mechanistically, incubation of isolated naïve CD4 + T cells with TLR8 triggered monocytes resulted in their differentiation into IL-21 + ICOS + BCL-6 + T FH in an IL-12 dependent manner. Furthermore, co-culture of these IL-21 producing T FH with autologous naïve B cells led to enhanced memory (CD19 + CD27 + ) and plasma B cell generation (CD19 + CD27 ++ CD38 + ) and IgG production. Importantly, in T FH from CHB patients treated with an oral TLR8 agonist, HBsAg-specific BCL-6, ICOS, IL-21 and CD40L expression and rescue of defective activation induced marker (AIM) response along with partial restoration of HBsAg-specific B cell ELISPOT response was evident. TLR8 agonism can thus enhance HBV-specific B cell responses in CHB patients by improving monocyte-mediated T FH function and may play a role in achieving HBV functional cure.

T follicular helper (Tfh) cells are a subset of CD4 T cells that provide critical signals to antigen-primed B cells in germinal centers to undergo proliferation, isotype switching, and somatic hypermutation to generate long-lived plasma cells and memory B cells during an immune response. The quantity and quality of Tfh cells therefore must be tightly controlled to prevent immune dysfunction in the form of autoimmunity and, on the other hand, immune deficiency. Both Tfh and B cell perturbations appear during HIV infection resulting in impaired antibody responses to vaccines such as seasonal trivalent influenza vaccine, also seen in biologic aging. Although many of the HIV-associated defects improve with antiretroviral therapy (ART), excess immune activation and antigen-specific B and T cell responses including Tfh function are still impaired in virologically controlled HIV-infected persons on ART. Interestingly, HIV infected individuals experience increased risk of age-associated pathologies. This review will discuss Tfh and B cell dysfunction in HIV infection and highlight the impact of chronic HIV infection and aging on Tfh-B cell interactions.

Weakened germinal center responses by the aged immune system result in diminished immunity against pathogens and reduced efficacy of vaccines. Prolonged contacts between activated B cells and CD4+ T cells are crucial to germinal center formation and T follicular helper cell (Tfh) differentiation, but it is unclear how aging impacts the quality of this interaction. Peptide immunization confirmed that aged mice have decreased expansion of antigen‐specific germinal center B cells and reduced antibody titers. Furthermore, aging was associated with accumulated Tfh cells, even in naïve mice. Despite increased numbers, aged Tfh had reduced expression of master transcription factor BCL6 and increased expression of the ectonucleotidase CD39. In vitro activation revealed that proliferative capacity was maintained in aged CD4+ T cells, but not the costimulatory molecule CD40L. When activated in vitro by aged antigen‐presenting cells, young CD4+ naïve T cells generated reduced numbers of activated cells with upregulated CD40L. To determine the contribution of cell‐extrinsic influences on antigen‐specific Tfh induction, young, antigen‐specific B and CD4+ T cells were adoptively transferred into aged hosts prior to peptide immunization. Transferred cells had reduced expansion and differentiation into germinal center B cell and Tfh and reduced antigen‐specific antibody titers when compared to young hosts. Young CD4+ T cells transferred aged hosts differentiated into Tfh cells with reduced PD‐1 and BCL6 expression, and increased CD39 expression, though they maintained their mitochondrial capacity. These results highlight the role of the lymphoid microenvironment in modulating CD4+ T cell differentiation, which contributes to impaired establishment and maintenance of germinal centers. Aging is associated with poor induction of germinal centers, organized lymphoid tissue structures that are important for infection and vaccination responses. CD4+ T cells provide help to B cells during germinal center induction, but the mechanisms by which they fail to support germinal centers are still unclear. Here we uncouple T cell‐intrinsic versus extrinsic changes with age that contribute to impaired CD4+ T‐cell activation and differentiation.

T follicular helper (Tfh) cells are crucially involved in the pathogenesis of autoimmune disorders, including Sjögren’s disease (SjD, also known as Sjögren’s syndrome), by promoting effector B cell responses and autoantibodies production. However, targeting Tfh cells remains challenging. In this study, we identified that calycosin (Caly), a natural flavonoid, effectively suppressed pathogenic Tfh cell responses, although it did not affect the plasmacytic differentiation of B cells. Under Tfh polarization conditions, Caly rapidly bound to the master transcription factor, BATF, in both human and murine CD4 + T cells and thus potently disrupted BATF-mediated Maf gene transcription. Methotrexate (MTX), a first-line medication in the treatment of autoimmune disorders, mainly suppresses B cell responses but fails to target Tfh cells. In a mouse model of experimental Sjögren’s syndrome (ESS) that we previously established, MTX synergized with Caly in attenuating the disease pathology and autoantibodies in ESS mice with chronic inflammation, with signs of disease remission. This immunomodulatory function was also validated in peripheral blood mononuclear cells from patients with SjD. Thus, Caly may serve as a novel inhibitor of BATF in suppressing Tfh-cell-mediated humoral autoimmunity and elicit a synergistic effect in combination with B-cell-targeting strategies.

Previous studies from our lab identified functional defects in antigen‐specific peripheral T follicular helper cells (pTfh), characterized by low IL‐21 and high IL‐2 production, contributing to non‐responsiveness to the influenza vaccine in both aging and HIV. This study investigated how IL‐21‐induced STAT3 and IL‐2‐induced STAT5 activation in pTfh cells affects vaccine responses in aging people with HIV (PWH) and those without HIV (PWoH). Ninety participants, including young (Y, ≤ 40 years) and old (O, ≥ 65 years) PWoH (YPWoH, n = 23; OPWoH, n = 25) and virally suppressed PWH (YPWH, n = 19; OPWH, n = 23), received the seasonal quadrivalent influenza vaccine. Samples were collected at pre‐vaccination (day 0) and at days 14 and 28 post‐vaccination. Participants were classified as vaccine responders (VR) or non‐responders (VNR) based on serum antibody titers against vaccine antigens using the hemagglutination inhibition assay. Phosphoflow cytometry was performed on pre‐vaccination PBMCs stimulated with IL‐21 or IL‐2, and high‐dimensional analysis was performed using OMIQ software. Peripheral Tfh cells of young individuals showed greater IL‐21‐induced STAT3, reduced IL‐2‐induced STAT5 activity, and a reduced frequency of IL‐2R+ pTfh cells compared to older individuals. IL‐21‐induced STAT3 in naïve CD4+ T cells in young participants correlated with the frequency of pTfh cells. Among VNR, IL‐2‐induced STAT5 in pTfh cells inversely correlated with day 28 vaccine titers. Our findings emphasize the essential role of IL‐21 and IL‐2‐induced STAT signaling in orchestrating the immune response to vaccination. As individuals age, IL‐2‐induced STAT5 signaling in pTfh increases, potentially hindering Tfh cell differentiation and function, which may result in weaker vaccine responses. Chronic immune activation and inflammation associated with aging and HIV skew Tfh signaling toward enhanced IL‐2–STAT5 activation, reinforcing IL‐2R expression through a positive feedback loop and suppressing Tfh helper differentiation programs, thereby contributing to impaired vaccine responsiveness.

This study investigates the pathogenic contributions of aquaporin-4 (AQP4)-specific follicular helper T (Tfh) and T helper 17 (Th17) cells in neuromyelitis optica spectrum disorder (NMOSD), utilizing newly established murine models based on adoptive transfer of antigen-specific T-cell populations. AQP4-knockout mice were immunized with the AQP4-derived peptide to generate AQP4-reactive Tfh and Th17 cells. These cells were subsequently isolated and adoptively transferred into wild-type recipient mice. At disease peak-defined by consistent neurological deficits-spinal cord and brain tissues were harvested for histopathological analysis, as well as immunohistochemistry. Central nervous system immune cell infiltration was quantified via flow cytometry. Total RNA was extracted from spinal cord tissue for bulk RNA sequencing; differentially expressed genes were validated using quantitative real-time PCR. Recipient mice that received AQP4-reactive Tfh or Th17 cells developed progressive hind-limb weakness, with Th17-transferred mice exhibiting significantly more severe clinical scores. Histopathological analyses revealed robust perivascular inflammation, parenchymal immune infiltration, and focal demyelination. Immunohistochemical quantification demonstrated significantly increased the optical density of CD3, B220, GFAP, IBA1, and CXCL9, alongside markedly decreased MBP expression. Flow cytometric profiling confirmed substantial infiltration of leukocytes and activated microglia/macrophages into the central nervous system (CNS). Transcriptomic analysis identified CXCL9 as one of the most upregulated chemokines in the spinal cord; its astrocytic origin was further corroborated by confocal immunofluorescence co-localization with GFAP. Our findings establish that AQP4-specific Tfh and Th17 cells are sufficient to drive key neuropathological features of NMOSD-including microglial reactivity, leukocyte recruitment, neuroinflammation, and demyelination- . The pronounced upregulation and astrocyte-derived expression of CXCL9 suggest its involvement in orchestrating CNS inflammation and position it as a potential contributor for NMOSD.

Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), has an important pathogenesis that lies in the self-amplifying inflammatory circuit formed by bidirectional interactions between dendritic cells (DCs) and T follicular helper (TFH) cells. This review elucidates that specific mature DC subsets in the intestinal inflammatory microenvironment drive TFH cell differentiation through synergistic co-stimulatory signals (CD80/CD86-CD28, OX40L-OX40) and cytokine networks (IL-12/STAT4/BCL-6, TGF-β/c-Maf/CXCR5); conversely, TFH-derived Lymphotoxin alpha 1 beta 2 (LTα1β2) activates stromal cell LTβR/NF-κB signaling pathway, inducing chemokine (CXCL13, CCL19, CCL21) production, thereby recruiting CCR7 + DC and CXCR5 + lymphocytes to form structural lymphoid clusters. Within these clusters, sustained DC-TFH cell interactions enhance TFH pathological effector functions (e.g., excessive IL-21 secretion), promote Th1/Th17 differentiation and weaken regulatory T cell inhibitory capacity, ultimately causing barrier destruction and tissue damage. Notably, while this pathogenic axis is active in both CD and UC, its cellular dynamics and microenvironment may exhibit disease-subtype distinctions. Current therapeutic strategies targeting this axis—including JAK inhibitors (e.g., upadacitinib), cytokine biologics (e.g., ustekinumab) and integrin blockers (e.g., vedolizumab)—achieve efficacy by interfering with DC-dependent TFH differentiation or TFH-mediated DC aggregation. Emerging evidence indicates traditional Chinese medicine active components (e.g., ginsenoside Rh2, curcumin) may intervene in this interaction through multi-pathway immunoregulation. However, utilizing single-cell and spatial transcriptomics to analyze spatial characteristics and disease-subtype-specific profiles of DC-TFH cell interactions remains key to developing next-generation therapies. While this axis provides a novel perspective for understanding immune dysregulation in IBD, its temporal role in disease initiation, crosstalk with other immune pathways, and translation from animal models to human disease remain challenges and future directions for the field.

Chronic antigenic stimulation can trigger the formation of interleukin 10 (IL-10)-producing T-regulatory type 1 (TR1) cells in vivo. We have recently shown that murine T-follicular helper (TFH) cells are precursors of TR1 cells and that the TFH-to-TR1 cell transdifferentiation process is characterized by the progressive loss and acquisition of opposing transcription factor gene expression programs that evolve through at least one transitional cell stage. Here, we use a broad range of bulk and single-cell transcriptional and epigenetic tools to investigate the epigenetic underpinnings of this process. At the single-cell level, the TFH-to-TR1 cell transition is accompanied by both, downregulation of TFH cell-specific gene expression due to loss of chromatin accessibility, and upregulation of TR1 cell-specific genes linked to chromatin regions that remain accessible throughout the transdifferentiation process, with minimal generation of new open chromatin regions. By interrogating the epigenetic status of accessible TR1 genes on purified TFH and conventional T-cells, we find that most of these genes, including Il10 , are already poised for expression at the TFH cell stage. Whereas these genes are closed and hypermethylated in Tconv cells, they are accessible, hypomethylated, and enriched for H3K27ac-marked and hypomethylated active enhancers in TFH cells. These enhancers are enriched for binding sites for the TFH and TR1-associated transcription factors TOX-2, IRF4, and c-MAF. Together, these data suggest that the TR1 gene expression program is genetically imprinted at the TFH cell stage.