Human Extrafollicular CD4+ Th Cells Help Memory B Cells Produce Igs

Kim, Sang Taek; Choi, Jin Young; Laínez, Begoña; Schulz, Vincent P.; Karas, David E.; Baum, Eric D.; Setlur, Jennifer; Gallagher, Patrick G.; Craft, Joe

doi:10.4049/jimmunol.1701217

Cited by 30 publications

(24 citation statements)

References 93 publications

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“…Similar to previous studies (17), the sorted CD4 + CXCR5 + PD-1 high cells, CD4 + CXCR5 + PD-1 + cells, CD4 + CXCR5 + PD-1 − cells, and CD4 + CXCR5 − cells from 4 HBV-LC patients or 4 HC donors were co-cultured with allogeneic or autologous CD19 + B cells at the ratio of 1:1 in RPMI-1640 medium containing 10% fetal bovine serum (FCS) and staphylococcal enterotoxin B (SEB) (100 ng/ml). Alternatively, rIL-21R-Fc chimera (10 μg/mL; R&D Systems, Minneapolis, MN) was added when the CD4 + CXCR5 + PD-1 high cells co-cultured with B cells (24).…”

Section: Methodssupporting

confidence: 92%

“…Splenic Tfh cells play key roles in T-dependent antibody responses (16). The interaction between Tfh cells and cognate B cells induces robust B cell proliferation and instructs them to undergo differentiation through CD40 engagement and IL-21 supply (17). The persistent activation of Tfh cells is required to promote broadly and affinity matured neutralizing antibodies throughout chronic viral infection, and to adapt specificity to emerging viral variants (18).…”

Section: Introductionmentioning

confidence: 99%

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Hyperactive Follicular Helper T Cells Contribute to Dysregulated Humoral Immunity in Patients With Liver Cirrhosis

Zhao

Shi

et al. 2019

Front. Immunol.

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Objectives: Liver cirrhosis (LC) is usually accompanied by cirrhosis associated immune dysfunction (CAID), including reduced naïve T cells and memory B cells. However, little is known regarding on follicular helper T (Tfh) cell compartments in cirrhotic patients, especially in the secondary lymphoid organs such as spleen. This study characterizes splenic Tfh cells and explores its association with humoral immunity and disease progression in cirrhotic patients. Methods: Using flow cytometry and histological staining, we analyzed the frequency and cytokine production of splenic Tfh cells from LC patients and healthy controls (HCs). Co-culture experiments of sorted Tfh and B cells were performed for functional analysis in vitro . The correlations between Tfh cells and disease progression markers as well as B cell subset perturbations were also examined. Results: PD-1 high ICOS + CXCR5 + Tfh cells were preferentially enriched in the spleen of cirrhotic patients, where they expressed higher levels of CXCR3 and produced more interleukin (IL)-21. Histologically, more splenic Tfh cells occupied the B cell follicular structure in LC patients where they shaped more active germinal centers (GCs) than those in HC spleens. In vitro , splenic Tfh cells in cirrhotic patients robustly induce plasma cell differentiation through IL-21 dependent manner. Finally, increased Tfh cell frequency is positively correlated with the plasma cells and disease severity in LC patients. Conclusions: We conclude that hyperactive Tfh cells contribute to dysregulated humoral immunity in patients with liver cirrhosis.

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Section: Methodssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Hyperactive Follicular Helper T Cells Contribute to Dysregulated Humoral Immunity in Patients With Liver Cirrhosis

Zhao

Shi

et al. 2019

Front. Immunol.

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“…125 Therefore, the enhanced helper function of blood borne cTfh cells has been suggested to be due to a recall of a previously committed cell fate. 133 Despite the increased interest in the functional role of Tfh-like memory cells, their exact origin is incompletely known. 129,131 This idea is supported by the finding that memory CD4 + T cells are found on the outer edge of the follicle where they presumably sample antigens displayed on subcapsular sinus (SCS) macrophages, while awaiting antigen recognition to be reactivated.…”

Section: Memory T Cell S With Tfh Cell P Otentialmentioning

confidence: 99%

“…132 A similar population of antigen-experienced cells was recently described in human tonsils as PSGL-1 hi CXCR5 hi PD-1 hi and was found at the T-B border colocalizing with memory B cells, suggesting their role in memory B cell reactivation upon antigenic recall. 133 Despite the increased interest in the functional role of Tfh-like memory cells, their exact origin is incompletely known. It has been shown repeatedly in adoptive transfer studies of cells expressing Tfh cell surface molecules (CXCR5 hi PD-1 hi PSGL-1 lo Ly6c lo ) and the canonical Tfh cell cytokine IL-21 (using an IL-21 reporter) that mature GC Tfh cells do not undergo global apoptosis during cell contraction following immune challenge, and can persist into the memory phase.…”

Section: Memory T Cell S With Tfh Cell P Otentialmentioning

confidence: 99%

T follicular helper cell heterogeneity: Time, space, and function

Song

Craft

2019

Immunological Reviews

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161

136

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Summary T follicular helper (Tfh) cells play a crucial role in orchestrating the humoral arm of adaptive immune responses. Mature Tfh cells localize to follicles in secondary lymphoid organs (SLOs) where they provide help to B cells in germinal centers (GCs) to facilitate immunoglobulin affinity maturation, class‐switch recombination, and generation of long‐lived plasma cells and memory B cells. Beyond the canonical GC Tfh cells, it has been increasingly appreciated that the Tfh phenotype is highly diverse and dynamic. As naive CD4+ T cells progressively differentiate into Tfh cells, they migrate through a variety of microanatomical locations to obtain signals from other cell types, which in turn alters their phenotypic and functional profiles. We herein review the heterogeneity of Tfh cells marked by the dynamic phenotypic changes accompanying their developmental program. Focusing on the various locations where Tfh and Tfh‐like cells are found, we highlight their diverse states of differentiation. Recognition of Tfh cell heterogeneity has important implications for understanding the nature of T helper cell identity specification, especially the plasticity of the Tfh cells and their ontogeny as related to conventional T helper subsets.

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“…Tfh differentiation is mainly regulated by the transcription factor, Bcl-6 [11]. Tfh cells can promote antigen-specific B cell activation, germinal center formation and humoral responses [12,13]. In addition, Tfh cells are involved in the pathogenic process of some autoimmune diseases [14-16] and participate in defensing against parasite infection [17,18].…”

Section: Introductionmentioning

confidence: 99%

ICOS enhances follicular T helper responses and deteriorates the pathogenic process of liver in mice infected withSchistosoma japonicum

Wang

Song

Wang

et al. 2020

Preprint

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23 Background: Humoral immune responses play an important role in mediating liver 24 granulomatous inflammation and fibrosis in schistosomiasis. Follicular helper T (Tfh) cells 25 have a central role in mediating humoral immune responses. Generation of Tfh cells depends 26 on inducible T cell costimulator (ICOS) signaling, but the underlying molecular mechanisms 27 are incompletely understood in pathogenesis of schistosomiasis. 28 Methodology/Principal Findings: We used a strain of ICOS-transgenic (Tg) mice to 29 test the degrees of liver granulomatous inflammation and fibrosis, the frequency of splenic 30 Tfh cells and soluble egg antigen-specific cytokine responses longitudinally in mice 31following Schistosoma japonicum (S. japonicum) infection. In comparison with that in 32 wide-type (WT) mice, significantly severer liver granulomatous inflammation and fibrosis 33 and higher mortality were observed in ICOS-Tg mice. Significantly higher frequency of 34 splenic Tfh cells was accompanied by significantly higher levels of Bcl-6 and CXCR5 35 expression in the livers of ICOS-Tg mice. Furthermore, significantly higher levels of 36 SEA-specific IL-4, IL-6, IL-10, IL-13, IL-17A, IL-21 and TGF-β1 responses, but lower 37 levels of IFN-responses were detected in ICOS-Tg mice, which were abrogated by 38 treatment with ICOS blockers in vitro. In addition, significantly higher levels of serum 39 anti-SEA IgG were detected in ICOS-Tg mice. 40 Conclusions/Significance: The ICOS-related signaling may promote the pathogenesis 41 of murine schistosomiasis by polarizing Tfh cells, which may be immune check points for the 42 prevention and intervention of schistosomiasis.43 3 3 Author summary 44 Granulomatous inflammation and fibrosis in the liver are the major pathogenic 45 characteristics of schistosomiasis. ICOS is crucial for the development of Tfh cells, which are 46 the key modulators of B cell activation and humoral immunity. However, the underlying 47 molecular mechanisms are incompletely understood in pathogenesis of schistosomiasis. Here, 48 our results showed that the ICOS over-expression would significantly induce severer liver 49 inflammation and fibrosis, higher frequency of splenic Tfh, higher levels of anti-SEA IgG as 50 well as imbalanced SEA-specific cytokine responses in ICOS-Tg mice. The findings 51 suggested that ICOS signaling may promote the pathogenesis of murine schistosoma-related 52 liver inflammation and fibrosis by polarizing Tfh cells. Potentially, ICOS signaling and Tfh 53 cells may be immune check points for the prevention and intervention of schistosomiasis. 54 55 4 4 Introduction 56 S. japonicum infection remains a problem for human health in developing countries. 57 During the pathogenesis of schistosomiasis, S. japonicum infection-related egg deposition can 58 recruit inflammatory infiltrates and cause granulomatous inflammation and fibrosis in the 59 liver [1,2]. More importantly, continual pathogenic process of inflammation and fibrosis in 60 the liver usually impairs its function, even leadin...

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Human Extrafollicular CD4+ Th Cells Help Memory B Cells Produce Igs

Cited by 30 publications

References 93 publications

Hyperactive Follicular Helper T Cells Contribute to Dysregulated Humoral Immunity in Patients With Liver Cirrhosis

Hyperactive Follicular Helper T Cells Contribute to Dysregulated Humoral Immunity in Patients With Liver Cirrhosis

T follicular helper cell heterogeneity: Time, space, and function

ICOS enhances follicular T helper responses and deteriorates the pathogenic process of liver in mice infected withSchistosoma japonicum

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