Oligoclonal expansion of IgG+ B cells along with Tfh cell response is associated with a better outcome in endometrial cancer.

Persistent Antigen and Germinal Center B Cells Sustain T Follicular Helper Cell Responses and Phenotype

TFH cells regulate antibody affinity and determine the outcomes of anaphylaxis

To investigate the effect of olfactory ecto-mesenchymal stem cell-derived exosomes (OE-MSC-Exos) on T follicular helper (Tfh) cell response and their implication in treating experimental Sjögrens syndrome (ESS). C57BL/6 mice were immunized with salivary glands (SG) proteins to induce ESS mouse model. OE-MSC-Exos were added to the Tfh cell polarization condition, and the proportion of Tfh cells was detected by FCM. The PD-L1 of OE-MSCs was silenced with small interfering RNA to extract siPD-L1-OE-MSC-Exos. We found that transfer of OE-MSC-Exos markedly attenuated disease progression and reduced Tfh cell response in mice with ESS. In culture, OE-MSC-Exos potently inhibited the differentiation of Tfh cells from naïve T cells. Moreover, OE-MSC-Exos expressed high level of the ligand for the programmed cell death protein 1 (PD-L1), knocking down PD-L1 expression in OE-MSC-Exos significantly decreased their capacity to suppress Tfh cell differentiation in vitro. Consistently, transfer of OE-MSC-Exos with PD-L1 knockdown exhibited profoundly diminished therapeutic effect in ESS mice, accompanied with sustained Tfh cell response and high levels of autoantibody production. Our results suggest that OE-MSC-Exos may exert their therapeutic effect in ameliorating ESS progression via suppressing Tfh cell response in a PD-L1-dependent manner.

Type I interferon (IFN-I) is highly prevalent in autoimmune disorders and is intricately involved in disease pathogenesis, including Sjögren's disease (SjD), also known as Sjögren's syndrome. Although the T follicular helper (Tfh) cell response has been shown to drive SjD development in a mouse model of experimental Sjögren's syndrome (ESS), the connection between IFN-I and the Tfh cell response remains unclear. As the activation of stimulator of interferon genes (STING) induces IFN-I production, we first demonstrated that mice deficient in STING or IFN-I signaling presented diminished Tfh cells and were completely resistant to ESS development. However, the STING-IFN-I axis does not directly influence Tfh cell differentiation. Instead, IFN-I signaling in B cells was essential for mounting Tfh cell responses, as evidenced in Cd19CreIfnar1flox mice, which also showed resistance to ESS development. Mechanistic analyses revealed that IFN-I drove CXCR5 expression in innate-like marginal zone B cells via the MEKK3-OCT2 axis, facilitating their migration into the follicular area. Additionally, IFN-I promoted interleukin-6 production in B cells via the MEKK3-ERK5 axis, resulting in hyperactive Tfh cell responses. In SjD patients, STING activation was predominantly observed in circulating CD14+ monocytes and was positively correlated with disease activity and effector T-cell responses. Pharmaceutical inhibition of either STING or IFNAR1 yielded moderate improvements in ESS mice with chronic inflammation, but combination therapy markedly improved outcomes and led to signs of disease remission. Our findings elucidate a novel mechanism by which IFN-I bridges innate and Tfh cell responses, suggesting new therapeutic avenues for SjD and related autoimmune disorders.

Follicular helper T cells (TFH cells), known as the primary “helpers” of the germinal center (GC) reaction, promote the humoral immune response to defend against various pathogens. Under conditions of infection by different types of pathogens, many shared transcription factors (TFs), such as Bcl-6, TCF-1, and Maf, are selectively enriched in pathogen-specific TFH cells, orchestrating TFH cell differentiation and function. In addition, TFH cells also coexpress environmentally associated TFs as their conventional T cell counterparts (such as T-bet, GATA-3, or ROR-γt, which are expressed in Th1, Th2, or Th17 cells, respectively). These features likely indicate both the lineage-specificity and environmental adaption of the TFH cell responses. However, the extent to which the TFH cell response relies on these environmentally specific TFs is not completely understood. Here, we found that T-bet was specifically expressed in Type I TFH cells but not Type II TFH cells. While dispensable for the early fate commitment of TFH cells, T-bet was essential for the maintenance of differentiated TFH cells, promoting their proliferation, and inhibiting their apoptosis during acute viral infection. Microarray analysis showed both similarities and differences in transcriptome dependency on T-bet in TFH and TH1 cells, suggesting the distinctive role of T-bet in TFH cells. Collectively, our findings reveal an important and specific supporting role for T-bet in type I TFH cell response, which can help us gain a deeper understanding of TFH cell subsets.

T follicular helper (Tfh) cells are a specialized subset of CD4+ T cells that aide in the production of high-affinity antibody (Ab) responses. In the absence of Tfh cells, there is impairment in the generation of protective Ab responses to pathogens. In autoimmune patients, however, the expansion of unwanted self-reactive Tfh cells favor auto-Ab responses and subsequent Ab-mediated pathology. Thus, understanding the factors that regulate the generation of Tfh cells is critical for developing more efficient vaccination strategies and for designing new therapeutic approaches to prevent Ab-mediated autoimmune diseases. In this regard, it is generally acknowledged that IL-2 inhibits CD4 T cells from differentiating into Tfh cells. Conversely, previous studies suggest that IL-6 signaling is required for normal Tfh cell responses. However, Tfh cells normally differentiate in the absence of IL-6 in some experimental models, suggesting that IL-6 is not absolutely necessary for Tfh cell formation. Thus, the exact role played by IL-6 in controlling Tfh cell responses remains elusive. Using an influenza infection model, we found that IL-6 is dispensable for the priming of influenza-specific Tfh cell precursors, but essential for the maintenance of the Tfh cells at the peak of the influenza immune response. Mechanistically, our results demonstrate that already differentiated Tfh cells produce large amounts of IL-2 in the GCs and that intrinsic IL-6 signaling is needed to antagonize the negative impact of IL-2 in the ongoing Tfh cell response. Collectively, our data demonstrate that IL-6 induces a program that allows for Tfh cells to produce IL-2 without succumbing to the deleterious effects of IL-2 on Tfh cell differentiation.

Allergen-specific immunotherapy modulates the balance of circulating Tfh and Tfr cells

Follicular helper T cells in immune homeostasis

Increased numbers of T follicular helper (Tfh) cells have been implicated in the development of autoimmune diseases including primary Sjögren's syndrome (pSS), but how the Tfh cell response is regulated during autoimmune pathogenesis remains largely unclear. Here, we first found negative correlations between IL-10+ regulatory B (Breg) cell numbers and Tfh cell responses and disease activity in patients with pSS and mice with experimental Sjögren's syndrome (ESS). Moreover, we detected high expression of IL-10 receptor on Tfh cells and their precursors in both humans and mice. In culture, IL-10 suppressed human and murine Tfh cell differentiation by promoting STAT5 phosphorylation. By using an adoptive transfer approach and two-photon live imaging, we found significantly increased numbers of Tfh cells with enhanced T cell homing into B cell follicles in the draining cervical lymph nodes of RAG-2-/- mice transferred with IL-10-deficient B cells during ESS development compared with those of RAG-2-/- mice transferred with wild-type B cells. In ESS mice, CD19+CD1dhiCD5+ Breg cells with decreased IL-10 production exhibited severely impaired suppressive effects on T cell proliferation. Consistently, CD19+CD24+CD38hi Breg cells from pSS patients showed significantly reduced IL-10 production with defective inhibitory function in the suppression of autologous Tfh cell expansion. Furthermore, the adoptive transfer of IL-10-producing Breg cells markedly suppressed the Tfh cell response and ameliorated ESS progression in ESS mice. Together, these findings demonstrate a critical role for IL-10-producing Breg cells in restraining the effector Tfh cell response during pSS development.

Increasing evidence highlights a critical role of T follicular helper (Tfh) cells in autoimmune pathogenesis. This study aimed to identify inflammatory cytokines involved in driving Tfh cell responses in systemic lupus erythematosus (SLE). The circulating Tfh frequencies and IFN-β levels were analyzed for correlations with disease activities in SLE patients. Both lupus mice with IFN-β treatment and Ifnar1-/- mice with lupus induction were assessed for Tfh cell responses and disease progression. Sorting-purified naïve CD4+T cells from Ifnar1-/- mice were adoptively transferred to lupus mice for monitoring Tfh cell differentiation in vivo. In culture, mouse CD4+T cells treated with IFN-β were examined for Tfh cell differentiation and intracellular signaling pathway. The underlying mechanism for IFN-β secretion by MDSCs was investigated by Co-immunoprecipitation and Western blotting. We found that increased Tfh cells with IFN-I inducible gene signatures correlated with disease activities in SLE patients. Consistently, IFN-β treatment markedly enhanced Tfh cell response and exacerbated disease progression in lupus mice. Moreover, mice with IFNAR1 deficiency exhibited attenuated lupus progression with significantly decreased Tfh response. Mechanistically, IFN-β activated IDO-Kyn-AhR axis to promote Tfh cell differentiation. Notably, expanded myeloid-derived suppressor cells (MDSCs) in lupus were found to produce high levels of IFN-β. Further studies showed that the autoantigen activated lymphocyte-derived DNA (ALD-DNA) stimulated IFN-β production by MDSCs via cGAS-STING-dependent pathway. These results have demonstrated a novel function of IFN-β in promoting Tfh cell response during lupus progression, which may facilitate the identification of new therapeutic targets for the treatment of SLE.

Blockade of Glucocorticoid-Induced Tumor Necrosis Factor–Receptor-Related Protein Signaling Ameliorates Murine Collagen-Induced Arthritis by Modulating Follicular Helper T Cells

Deficiency of CBL and CBLB ubiquitin ligases leads to hyper T follicular helper cell responses and lupus by reducing BCL6 degradation

Malaria remains a significant global public health problem. T follicular helper (Tfh) cells, a subset of CD4+ T cells, have the capacity to regulate B cells, plasma cells, and antibody production, among other functions. Myeloid-derived suppressor cells (MDSCs) possess strong immunosuppressive abilities and can negatively regulate various immune responses. However, the role of MDSCs in inhibiting Tfh-cell responses during Plasmodium infection remains unclear. In this study, we investigated the regulatory effect of MDSCs on Tfh cell-mediated immune responses upon Plasmodium infection. We found that the numbers of MDSCs increased upon Plasmodium infection. Further mechanism study revealed that MDSC-derived Arg-1 and PD-L1 prevented Tfh cell proliferation and activation. Conversely, the addition of nor-NOHA or anti-PD-L1 monoclonal antibodies enhanced the proliferation and activation of Tfh cells, indicating that the inhibitory effect of MDSCs on Tfh cells was dependent on Arg-1 and PD-1/PD-L1. Invivo depletion of MDSCs enhanced Tfh-cell responses and antibody production, as well as relieved symptoms of infected mice and improved their survival rates. These findings provide insights into the immunosuppressive role of MDSCs in inhibiting Tfh cell immune responses and further impairing humoral immunity. Our study provides new strategies for malaria prevention and control.

IL-2 contributes to cirrhosis-associated immune dysfunction by impairing follicular T helper cells in advanced cirrhosis

Heterogeneous Tfh cell populations that develop during enteric helminth infection predict the quality of type 2 protective response