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Understanding the intricate relationship between peripheral blood immune profiles and the inflammatory environment within affected tissues is pivotal for uncovering mechanisms driving autoimmune diseases. This study aimed to characterize CD4 + T cell subsets in peripheral blood that mirror the immunological activation of labial salivary glands (LSG) infiltrating T cells in primary Sjögren’s disease (pSjD). Using multicolor flow cytometry and T cell receptor (TCR) sequencing, we identified CXCR3 + CXCR5 + T follicular helper 1 (Tfh1) cells as significantly elevated in the circulation of pSjD patients and even more prominently increased in the LSG, with blood PD-1 + ICOS + Tfh1 cells positively correlating with titers of antinuclear, anti-SS-A, and anti-SS-B antibodies. In contrast, CXCR3 + CXCR5 − Th1 cells were enriched in LSG but reduced in circulation. TCR analysis demonstrated that circulating Tfh1 cells shared a notable clonal similarity with LSG T cells. In the LSG, cytokines such as IL-6, IL-12, IL-21, and TGF-β were upregulated, with TGF-β and TCR recognition promoting Tfh1 differentiation. This microenvironment led to increased production of IL-2, TNF-α, and IL-21, promoting the expansion of CD19 + CD38 + B cells. These findings support the notion that circulating activated Tfh1 cells partially mirror glandular T cell activation and highlight TGF-β as a driver of Tfh1 differentiation, presenting a potential therapeutic target.

Follicular helper T cells (Tfh) are a Th cell subset that directly assists B cells in functioning, and their development is regulated by various factors. Among them, the initial regulation leads to phenotypic heterogeneity, while the regulation of their migration process results in spatial heterogeneity. The phenotypic heterogeneity is manifested by the presence of Tfh subsets with characteristics helper T cells (Th) of other lineages, namely Tfh1, Tfh2, and Tfh17, with different transcriptional programs and secrete distinct cytokines, potentially possessing different functions. The spatial heterogeneity is mainly manifested by the positional relationship between Tfh and germinal centers (GC), which are mainly divided into GC-Tfh, follicular mantle Tfh, and circulating Tfh, possibly reflecting the process of Tfh occurrence. This review summarizes the spatial and phenotypic heterogeneity of Tfh cells, and suggests a Tfh cell type framework with nodes of previous studied cell types and the edges of switching between specific celltypes, which is affected by the summation of imprinted plasticity part and de novo plasticity part in Tfh development, connecting the hypothesis Crotty et al. proposed in 2018. Discrete cell type is still eligible in qualifying the diseases state and quantifying the activity and severity of diseases, but it could also be beneficial to look Tfh from the view of cell states and expression programs, which, in the future studies, might better model the through process of Tfh development and unifying the contradiction caused by separate Tfh cell type view.

Good's syndrome (GS) is a rare acquired immunodeficiency defined by the co-occurrence of thymoma and hypogammaglobulinemia. Follicular helper T (Tfh) cells, a specialized CD4+ T cell subset, play a critical role in supporting B-cell antibody production. The status and characteristics of Tfh cells in GS, however, remain largely unexplored. This study utilized flow cytometry to analyze CD4+CXCR5+ T cells, along with Tfh1 (CXCR3+CCR6-), Tfh2 (CXCR3-CCR6-), and Tfh17 (CXCR3-CCR6+) subsets, in three GS patients compared to twenty healthy controls (HCs). Serum levels of Th1/Th2/Th17 cytokines were also assessed. The cohort included a 45-year-old female and a 70-year-old female, both with type AB thymoma, and a 47-year-old male with type A thymoma. All patients exhibited markedly reduced serum IgG levels (0.87 g/L, 1.44 g/L, 3.0 g/L) and a profound reduction or absence of peripheral B cells (0%, 0%, 3.7%). The proportions of CD4+CXCR5+ T cells and total Tfh cells in two patients (Cases 1 & 2) were comparable to HCs, while a significant increase was noted in the third patient (Case 3). A key finding was a consistent and drastic reduction in CXCR3+CCR6- Tfh1 cells across all patients, whereas Tfh2 cell frequencies were significantly elevated. Tfh17 cell percentages and Th1/Th2/Th17 cytokine profiles showed no significant alterations. Our findings reveal, for the first time, a pronounced decrease in circulating CXCR3+ Tfh1 cells in GS patients, suggesting a potential role for this specific immune imbalance in the disease's immunopathogenesis.

T follicular helper CD4 cells (Tfh) are essential for the development and maintenance of germinal center (GC) reactions, a critical process that promotes the generation of long-lived high affinity humoral immunity. It is becoming increasingly evident that GC-Tfh cells are heterogeneous in nature with some cellular characteristics associated with a Th1, Th2, and Th17 phenotype. Emerging studies suggest that GC-Tfh cells are directed to differentiate into distinct phenotypes during chronic HIV/SIV infection and these changes in GC-Tfh cells can greatly impact the B cell response and subclass of antibodies generated. Studies in HIV-infected humans have shown that certain Tfh phenotypes are associated with the generation of broadly neutralizing antibody responses. Moreover, the susceptibility of particular GC-Tfh subsets to HIV infection within the secondary lymphoid sites can also impact GC-Tfh/B cell interactions. In this review, we discuss the recent advances that show Tfh heterogeneity during chronic HIV/SIV infection. In particular, we will discuss the dynamics of GC-Tfh cells, their altered differentiation state and function, and their impact on B cell responses during HIV/SIV infection. In addition, we will also discuss the potential role of a recently described novel subset of follicular homing CXCR5 CD8 T cells (Tfc) and their importance in contributing to control of chronic HIV/SIV infection. A better understanding of the mechanistic role of follicular homing CD4 and CD8 T cells during HIV/SIV infection will aid in the design of vaccines and therapeutic strategies to prevent and treat HIV/AIDS.

Humoral immunity is a critical effector arm for protection against malaria but develops only slowly after repeated infections. T cell-mediated regulatory dynamics affect the development of antibody responses to Plasmodium parasites. Here, we hypothesize that T follicular helper cell (TFH) polarization generated by repeated Plasmodium asexual blood-stage infections delays the onset of protective humoral responses. IFN-γ production promotes polarization toward TFH1 and increased generation of regulatory follicular helper cells (TFR). Delineating the mechanisms that drive TH1 polarization will provide clues for appropriate induction of lasting, protective immunity against malaria.

Gout is a chronic disease characterized by the deposition of monosodium urate (MSU) crystals in tissue. Study with a focus on adaptive immune response remains to be understood although innate immune response has been reported extensively in gout etiology. Our study attempted to investigate the association of gout-related immune cell imbalance with clinical features and comorbidity with renal impairment and the implicated pathogenesis the assessment of T and B cell subsets in different activity phases or with immune effects combined with the analyses of clinical parameters. Fifty-eight gout patients and 56 age- and sex-matched healthy individuals were enrolled. To learn the roles of circulating T cells, a lymphocyte profile incorporating 32 T cell subsets was tested from isolated freshly peripheral blood monocyte cells (PBMCs) with multiple-color flow cytometry. Furthermore, the collected clinical features of participants were used to analyze the characteristics of these differential cell subsets. Stratified on the basis of the level of creatinine (Cr, enzymatic method), all patients were categorized into Cr (Cr ≤ 116 μmol/L) and Cr (Cr > 116 μmol/L) groups to exploit whether these gout-associated T cell subsets were functional in gout-targeted kidney dysfunction. The differentiation of B cells was investigated in gout patients. Our results show that CD 4 T cells, Th2 cells, and Tc2 cells were upregulated, whereas Tc17 cells were downregulated. Tfh cells skewed toward the polarization of Tfh2 cells. Specifically, Tfh2 cells increased, but Tfh1 cells decreased, accompanied with aging for gout patients, suggesting that age might trigger the skewing of Tfh1/Tfh2 cell subsets to influence gout development. Moreover, Tfh2 cells were connected to renal dysfunction as well. No alterations of B cell subsets were observed in patients when compared to controls. Our data demonstrate age-specific dysfunctions of Tfh1/2 cells in gout occurrence, and Tfh2 cell upregulation is associated with gout-targeted renal dysfunction. However, Tfh2 cells may function in auto-inflammatory gout independent of helping B differentiation, and an in-depth study remains to be conducted.