scholarly journals Sphingosine-1-phosphate receptor 2 is critical for follicular helper T cell retention in germinal centers

2014 ◽  
Vol 211 (7) ◽  
pp. 1297-1305 ◽  
Author(s):  
Saya Moriyama ◽  
Noriko Takahashi ◽  
Jesse A. Green ◽  
Shohei Hori ◽  
Masato Kubo ◽  
...  
Keyword(s):  
T Cells ◽  
Germinal Center ◽  
Molecular Mechanisms ◽  
Germinal Centers ◽  
Antibody Responses ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Sphingosine 1 Phosphate ◽  
Follicular Helper T Cell ◽  
Cell Follicle

Follicular helper T (Tfh) cells access the B cell follicle to promote antibody responses and are particularly important for germinal center (GC) reactions. However, the molecular mechanisms of how Tfh cells are physically associated with GCs are incompletely understood. We report that the sphingosine-1-phosphate receptor 2 (S1PR2) gene is highly expressed in a subpopulation of Tfh cells that localizes in GCs. S1PR2-deficient Tfh cells exhibited reduced accumulation in GCs due to their impaired retention. T cells deficient in both S1PR2 and CXCR5 were ineffective in supporting GC responses compared with T cells deficient only in CXCR5. These results suggest that S1PR2 and CXCR5 cooperatively regulate localization of Tfh cells in GCs to support GC responses.

Th17 Cells and Associated Cytokines in Inflammation and Cancer

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-5-SCI-5
Author(s):  
Chen Dong
Keyword(s):  
T Cells ◽  
Germinal Center ◽  
Th17 Cells ◽  
The Other ◽  
Th Cells ◽  
Tissue Inflammation ◽  
Tfh Cells ◽  
Follicular Helper ◽  
And Function ◽  
Th1 And Th2

Abstract Abstract SCI-5 CD4+ T cells, upon activation, differentiate into cytokine-producing effector helper T (TH) cells. In addition to TH1 and TH2 lineage cells, additional TH subsets, including TH17 and T follicular helper (Tfh) cells have been identified. TH17 cells produce IL-17, IL-17F, IL-21, and IL-22 and mediate tissue inflammation. TH17 cells play protective or pathogenic roles in cancer, depending on the context. On the other hand, Tfh cells produce IL-21 and regulate germinal center reactions. Tfh cells may play a role in some forms of lymphoma. I will discuss on the regulation and function of these two subsets of T cells in the context of cancer. Disclosures: Dong: Ono: Consultancy; Tempero: Consultancy; Genentech: Honoraria; GSK: Consultancy; AnaptysBio: Consultancy.

scholarly journals A distinct subpopulation of CD25− T-follicular regulatory cells localizes in the germinal centers

2017 ◽  
Vol 114 (31) ◽  
pp. E6400-E6409 ◽  
Author(s):  
James Badger Wing ◽  
Yohko Kitagawa ◽  
Michela Locci ◽  
Hannah Hume ◽  
Christopher Tay ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
Germinal Center ◽  
Germinal Centers ◽  
Regulatory Cells ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Distinct Subpopulation ◽  
Wide Range ◽  
Multistep Process

T-follicular helper (Tfh) cells differentiate through a multistep process, culminating in germinal center (GC) localized GC-Tfh cells that provide support to GC-B cells. T-follicular regulatory (Tfr) cells have critical roles in the control of Tfh cells and GC formation. Although Tfh-cell differentiation is inhibited by IL-2, regulatory T (Treg) cell differentiation and survival depend on it. Here, we describe a CD25− subpopulation within both murine and human PD1+CXCR5+Foxp3+ Tfr cells. It is preferentially located in the GC and can be clearly differentiated from CD25+ non–GC-Tfr, Tfh, and effector Treg (eTreg) cells by the expression of a wide range of molecules. In comparison to CD25+ Tfr and eTreg cells, CD25− Tfr cells partially down-regulate IL-2–dependent canonical Treg features, but retain suppressive function, while simultaneously up-regulating genes associated with Tfh and GC-Tfh cells. We suggest that, similar to Tfh cells, Tfr cells follow a differentiation pathway generating a mature GC-localized subpopulation, CD25− Tfr cells.

scholarly journals ICOS expression is required for maintenance but not the formation of germinal centers in the spleen in response to P. yoelii infection.

2022 ◽  
Author(s):  
Kara A. O’Neal ◽  
Leah E. Latham ◽  
Enatha Ntirandekura ◽  
Camille L. Foscue ◽  
Jason S. Stumhofer
Keyword(s):  
Germinal Center ◽  
Primary Infection ◽  
Germinal Centers ◽  
Affinity Maturation ◽  
Infection Model ◽  
Wild Type ◽  
Plasmodium Chabaudi ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Functional Defects

Inducible T cell co-stimulator (ICOS) plays a key role in the differentiation and maintenance of follicular helper T (Tfh) cells and thus germinal center (GC) formation. Previously, our lab showed in a Plasmodium chabaudi infection model that Icos -/- mice were significantly impaired in their ability to form GCs despite a persistent infection and thus a continued antigen (Ag) load. Here, we show that resolution of a primary infection with P. yoelii , was delayed in Icos -/- mice. This phenotype was associated with a reduction in the accumulation of Tfh-like and GC Tfh cells and an early deficiency in Ag-specific antibody (Ab) production. However, Icos -/- mice could form GCs, though they were less frequent in number than in wild-type (WT) mice. Nonetheless, the Ag-specific Abs from Icos -/- mice lacked signs of affinity maturation, suggesting functional defects associated with these GCs. Eventually, these GC structures dissipated more rapidly in Icos -/- mice than in WT mice. Moreover, the ability of Icos -/- mice to form these GC structures is not reliant on the high Ag load associated with P. yoelii infections, as GC formation was preserved in Icos -/- mice treated with atovaquone. Finally, mice were unable to form secondary GCs in the absence of ICOS after re-challenge. Overall, these data demonstrate the necessity of ICOS in the maintenance of Tfh cells, the formation and maintenance of sufficient numbers of functioning GCs, and the ability to generate new GC structures after re-infection with P. yoelii .

scholarly journals The transforming growth factor beta signaling pathway is critical for the formation of CD4 T follicular helper cells and isotype-switched antibody responses in the lung mucosa

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Heather D Marshall ◽  
John P Ray ◽  
Brian J Laidlaw ◽  
Nianzhi Zhang ◽  
Dipika Gawande ◽  
...  
Keyword(s):  
T Cells ◽  
Transforming Growth Factor Beta ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Antibody Responses ◽  
T Follicular Helper Cells ◽  
High Affinity ◽  
Tfh Cells ◽  
Helper Cells ◽  
Follicular Helper

T follicular helper cells (Tfh) are crucial for the initiation and maintenance of germinal center (GC) reactions and high affinity, isotype-switched antibody responses. In this study, we demonstrate that direct TGF-β signaling to CD4 T cells is important for the formation of influenza-specific Tfh cells, GC reactions, and development of isotype-switched, flu-specific antibody responses. Early during infection, TGF-β signaling suppressed the expression of the high affinity IL-2 receptor α chain (CD25) on virus-specific CD4 T cells, which tempered IL-2 signaling and STAT5 and mammalian target of rapamycin (mTOR) activation in Tfh precursor CD4 T cells. Inhibition of mTOR allowed for the differentiation of Tfh cells in the absence of TGF-βR signaling, suggesting that TGF-β insulates Tfh progenitor cells from IL-2-delivered mTOR signals, thereby promoting Tfh differentiation during acute viral infection. These findings identify a new pathway critical for the generation of Tfh cells and humoral responses during respiratory viral infections.

scholarly journals B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells

2011 ◽  
Vol 208 (7) ◽  
pp. 1377-1388 ◽  
Author(s):  
Sau K. Lee ◽  
Robert J. Rigby ◽  
Dimitra Zotos ◽  
Louis M. Tsai ◽  
Shimpei Kawamoto ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Antibody Responses ◽  
B Cell Differentiation ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Microbial Infections

T follicular helper cells (Tfh cells) localize to follicles where they provide growth and selection signals to mutated germinal center (GC) B cells, thus promoting their differentiation into high affinity long-lived plasma cells and memory B cells. T-dependent B cell differentiation also occurs extrafollicularly, giving rise to unmutated plasma cells that are important for early protection against microbial infections. Bcl-6 expression in T cells has been shown to be essential for the formation of Tfh cells and GC B cells, but little is known about its requirement in physiological extrafollicular antibody responses. We use several mouse models in which extrafollicular plasma cells can be unequivocally distinguished from those of GC origin, combined with antigen-specific T and B cells, to show that the absence of T cell–expressed Bcl-6 significantly reduces T-dependent extrafollicular antibody responses. Bcl-6+ T cells appear at the T–B border soon after T cell priming and before GC formation, and these cells express low amounts of PD-1. Their appearance precedes that of Bcl-6+ PD-1hi T cells, which are found within the GC. IL-21 acts early to promote both follicular and extrafollicular antibody responses. In conclusion, Bcl-6+ T cells are necessary at B cell priming to form extrafollicular antibody responses, and these pre-GC Tfh cells can be distinguished phenotypically from GC Tfh cells.

scholarly journals The Development of Optimally Responsive Plasmodium-specific CD73+CD80+ IgM+ Memory B cells Requires Intrinsic BCL6 expression but not CD4+ Tfh cells

2019 ◽  
Author(s):  
Gretchen Harms Pritchard ◽  
Akshay T. Krishnamurty ◽  
Jason Netland ◽  
E. Nicole Arroyo ◽  
Kennidy K. Takehara ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Plasma Cells ◽  
Germinal Centers ◽  
Memory B Cells ◽  
Effector Cells ◽  
High Affinity ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Bcl6 Expression

SummaryHumoral immunity depends upon the development of long-lived, antibody-secreting plasma cells and rapidly responsive memory B cells (MBCs). The differentiation of high affinity, class-switched MBCs after immunization is critically dependent upon BCL6 expression in germinal center (GC) B cells and CD4+ T follicular helper (Tfh) cells. It is less well understood how more recently described MBC subsets are generated, including the CD73+CD80+ IgM+ MBCs that initially form antibody-secreting effector cells in response to a secondary Plasmodium infection. Herein, we interrogated how BCL6 expression in both B and CD4+ T cells influenced the formation of heterogeneous Plasmodium-specific MBC populations. All Plasmodium-specific CD73+CD80+ MBCs required BCL6 expression for their formation, suggesting germinal center dependence. Further dissection of the CD4+ T and B cell interactions however revealed that somatically hypermutated CD73+CD80+ IgM+ MBCs can form not only in the absence of germinal centers, but also in the absence of CXCR5+ CD4+ Tfh cells.

scholarly journals IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells

2010 ◽  
Vol 207 (13) ◽  
pp. 2895-2906 ◽  
Author(s):  
Marcel Batten ◽  
Nandhini Ramamoorthi ◽  
Noelyn M. Kljavin ◽  
Cindy S. Ma ◽  
Jennifer H. Cox ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Germinal Center ◽  
Dependent Manner ◽  
High Affinity ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Cell Clones

Maturation and selection of high-affinity B cell clones in the germinal center (GC) relies on support from T follicular helper (TFH) cells. TFH cells are characterized by their localization to the B cell follicle and their high expression of the costimulatory molecules ICOS and PD1 and the cytokine IL-21, which promotes immunoglobulin (Ig) class switching and production by B cells. We show that the heterodimeric cytokine IL-27 is critical for the function of TFH cells and for normal and pathogenic GC responses. IL-27 signaling to T cells results in the production of IL-21, a known autocrine factor for the maintenance of TFH cells, in a STAT3-dependent manner. IL-27 also enhances the survival of activated CD4+ T cells and the expression of TFH cell phenotypic markers. In vivo, expression of the IL-27Rα chain is required to support IL-21 production and TFH cell survival in a T cell–intrinsic manner. The production of high-affinity antibodies is reduced, and pristane-elicited autoantibodies and glomerulonephritis are significantly diminished, in Il27ra−/− mice. Together, our data show a nonredundant role for IL-27 in the development of T cell–dependent antibody responses.

scholarly journals ICOS expression is required for maintenance but not the formation of germinal centers in the spleen in response to P. yoelii infection.

2021 ◽  
Author(s):  
Jason Stumhofer ◽  
Kara A O'Neal ◽  
Leah E Latham ◽  
Enatha Ntirandekura ◽  
Camille L Foscue
Keyword(s):  
Germinal Center ◽  
Primary Infection ◽  
Germinal Centers ◽  
Affinity Maturation ◽  
Infection Model ◽  
Wild Type ◽  
Plasmodium Chabaudi ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Functional Defects

Inducible T cell co-stimulator (ICOS) plays a key role in the differentiation and maintenance of follicular helper T (Tfh) cells and thus germinal center (GC) formation. Previously, our lab showed in a Plasmodium chabaudi infection model that Icos-/- mice did not form GCs despite a persistent infection and thus a continued antigen (Ag) load. Here, we show that resolution of a primary infection with P. yoelii, was delayed in Icos-/- mice. This phenotype was associated with a reduction in the accumulation of Tfh-like and GC Tfh cells and an early deficiency in Ag-specific antibody (Ab) production. However, Icos-/- mice maintained their ability to form GCs, though they were less frequent in number than in wild-type (WT) mice. Furthermore, while Ab production in Icos-/- mice matched that of WT mice after the infection cleared, the Abs lacked signs of affinity maturation, suggesting functional defects associated with these GCs. Eventually, these GC structures dissipated more rapidly in Icos-/-mice than in WT mice. Moreover, the ability of Icos-/- mice to form these GC structures is not reliant on the high Ag load associated with P. yoelii infections, as GC formation was preserved in Icos-/- mice treated with early with atovaquone. Finally, mice were unable to form secondary GCs in the absence of ICOS after re-challenge. Overall, these data demonstrate the necessity of ICOS in the maintenance of Tfh cells, the formation and maintenance of sufficient numbers of functioning GCs, and the ability to generate new GC structures after re-infection with P. yoelii.

scholarly journals Germinal Center T follicular helper (GC-Tfh) cell impairment in chronic HIV infection involves c-Maf signaling

2021 ◽  
Vol 17 (7) ◽  
pp. e1009732
Author(s):  
Marita Chakhtoura ◽  
Mike Fang ◽  
Rafael Cubas ◽  
Margaret H. O’Connor ◽  
Carmen N. Nichols ◽  
...  
Keyword(s):  
B Cells ◽  
Hiv Infection ◽  
Germinal Center ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Cell Functions ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Factor C ◽  
Anti Hiv

We have recently demonstrated that the function of T follicular helper (Tfh) cells from lymph nodes (LN) of HIV-infected individuals is impaired. We found that these cells were unable to provide proper help to germinal center (GC)-B cells, as observed by altered and inefficient anti-HIV antibody response and premature death of memory B cells. The underlying molecular mechanisms of this dysfunction remain poorly defined. Herein, we have used a unique transcriptional approach to identify these molecular defects. We consequently determined the transcriptional profiles of LN GC-Tfh cells following their interactions with LN GC-B cells from HIV-infected and HIV-uninfected individuals, rather than analyzing resting ex-vivo GC-Tfh cells. We observed that proliferating GC-Tfh cells from HIV-infected subjects were transcriptionally different than their HIV-uninfected counterparts, and displayed a significant downregulation of immune- and GC-Tfh-associated pathways and genes. Our results strongly demonstrated that MAF (coding for the transcription factor c-Maf) and its upstream signaling pathway mediators (IL6R and STAT3) were significantly downregulated in HIV-infected subjects, which could contribute to the impaired GC-Tfh and GC-B cell functions reported during infection. We further showed that c-Maf function was associated with the adenosine pathway and that the signaling upstream c-Maf could be partially restored by adenosine deaminase -1 (ADA-1) supplementation. Overall, we identified a novel mechanism that contributes to GC-Tfh cell impairment during HIV infection. Understanding how GC-Tfh cell function is altered in HIV is crucial and could provide critical information about the mechanisms leading to the development and maintenance of effective anti-HIV antibodies.

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