The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo

Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
The Journal of Immunology (Impact Factor: 4.92). 09/2005; 175(4):2340-8. DOI: 10.4049/jimmunol.175.4.2340
Source: PubMed


ICOS is a new member of the CD28 family of costimulatory molecules that is expressed on activated T cells. Its ligand B7RP-1 is constitutively expressed on B cells. Although the blockade of ICOS/B7RP-1 interaction inhibits T cell-dependent Ab production and germinal center formation, the mechanism remains unclear. We examined the contribution of ICOS/B7RP-1 to the generation of CXCR5+ follicular B helper T (T(FH)) cells in vivo, which preferentially migrate to the B cell zone where they provide cognate help to B cells. In the spleen, anti-B7RP-1 mAb-treated or ICOS-deficient mice showed substantially impaired development of CXCR5+ T(FH) cells and peanut agglutinin+ germinal center B cells in response to primary or secondary immunization with SRBC. Expression of CXCR5 on CD4+ T cells was associated with ICOS expression. Adoptive transfer experiments showed that the development of CXCR5+ T(FH) cells was enhanced by interaction with B cells, which was abrogated by anti-B7RP-1 mAb treatment. The development of CXCR5+ T(FH) cells in the lymph nodes was also inhibited by the anti-B7RP-1 mAb treatment. These results indicated that the ICOS/B7RP-1 interaction plays an essential role in the development of CXCR5+ T(FH) cells in vivo.

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    • "Of note, the majority of activated CXCR3 + Tfh cells were double positive for these markers (Figures S3A–S3C), indicating that this population is homogeneously activated. Besides the crucial role ICOS plays in Tfh development (Akiba et al., 2005) and function (Vogelzang et al., 2008), recent studies suggest that ICOS-expressing Tfh cells migrate toward B cells expressing ICOS ligand (ICOS-L) to initiate the formation of GCs (Xu et al., 2013). Interestingly, acute malaria was associated with a significant increase in ICOS expression only on CXCR3 + Tfh cells (Figure 4D). "
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    ABSTRACT: Malaria-specific antibody responses are short lived in children, leaving them susceptible to repeated bouts of febrile malaria. The cellular and molecular mechanisms underlying this apparent immune deficiency are poorly understood. Recently, T follicular helper (Tfh) cells have been shown to play a critical role in generating long-lived antibody responses. We show that Malian children have resting PD-1+CXCR5+CD4+ Tfh cells in circulation that resemble germinal center Tfh cells phenotypically and functionally. Within this population, PD-1+CXCR5+CXCR3− Tfh cells are superior to Th1-polarized PD-1+CXCR5+CXCR3+ Tfh cells in helping B cells. Longitudinally, we observed that malaria drives Th1 cytokine responses, and accordingly, the less-functional Th1-polarized Tfh subset was preferentially activated and its activation did not correlate with antibody responses. These data provide insights into the Tfh cell biology underlying suboptimal antibody responses to malaria in children and suggest that vaccine strategies that promote CXCR3− Tfh cell responses may improve malaria vaccine efficacy.
    Cell Reports 10/2015; 13(2). DOI:10.1016/j.celrep.2015.09.004 · 8.36 Impact Factor
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    • "The role of cognate B cells regarding the differentiation of Tfh cells has been initially validated by several studies. Deficiency of not only B cells but also various B cell functional molecules, CD19, CD40, major histocompatibility complex (MHC) class II, and ICOSL, results in the decreased number of Tfh cells (Akiba et al., 2005; Deenick et al., 2010; Haynes et al., 2007; Johnston et al., 2009). In addition, the interaction between activated CD4 + T cells and cognate B cells via SAP, a cytoplasmic adaptor protein of the SLAM family, was shown to be critical in Tfh cell generation (Cannons et al., 2010). "
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    ABSTRACT: Recent studies on T follicular helper (Tfh) cells have significantly advanced our understanding of T cell-dependent B cell responses. However, little is known about the early stage of Tfh cell commitment by dendritic cells (DCs), particularly by the conventional CD8α(+) and CD8α(-) DC subsets. We show that CD8α(-) DCs localized at the interfollicular zone play a pivotal role in the induction of antigen-specific Tfh cells by upregulating the expression of Icosl and Ox40l through the non-canonical NF-κB signaling pathway. Tfh cells induced by CD8α(-) DCs function as true B cell helpers, resulting in significantly increased humoral immune responses against various human pathogenic antigens, including Yersinia pestis LcrV, HIV Gag, and hepatitis B surface antigen. Our findings uncover a mechanistic role of CD8α(-) DCs in the initiation of Tfh cell differentiation and thereby provide a rationale for investigating CD8α(-) DCs in enhancing antigen-specific humoral immune responses for improving vaccines and therapeutics. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 06/2015; 11(12). DOI:10.1016/j.celrep.2015.05.042 · 8.36 Impact Factor
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    • "The two closely related co-stimulators CD28 and inducible T cell co-stimulator (ICOS) are both known to be important for T cell–dependent B cell responses. If appropriate co-stimulation is lacking, mice develop very small GCs and have strongly reduced numbers of TFH cells (Walker et al., 1999; McAdam et al., 2001; Tafuri et al., 2001; Akiba et al., 2005; Linterman et al., 2009; Platt et al., 2010). A similar picture can be observed in ICOS-deficient patients, who present with the clinical phenotype of common variable immunodeficiency (Grimbacher et al., 2003; Bossaller et al., 2006). "
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    ABSTRACT: The co-stimulators ICOS (inducible T cell co-stimulator) and CD28 are both important for T follicular helper (TFH) cells, yet their individual contributions are unclear. Here, we show that each molecule plays an exclusive role at different stages of TFH cell development. While CD28 regulated early expression of the master transcription factor Bcl-6, ICOS co-stimulation was essential to maintain the phenotype by regulating the novel TFH transcription factor Klf2 via Foxo1. Klf2 directly binds to Cxcr5, Ccr7, Psgl-1, and S1pr1, and low levels of Klf2 were essential to maintain this typical TFH homing receptor pattern. Blocking ICOS resulted in relocation of fully developed TFH cells back to the T cell zone and reversion of their phenotype to non-TFH effector cells, which ultimately resulted in breakdown of the germinal center response. Our study describes for the first time the exclusive role of ICOS and its downstream signaling in the maintenance of TFH cells by controlling their anatomical localization in the B cell follicle.
    Journal of Experimental Medicine 02/2015; 212(2). DOI:10.1084/jem.20141432 · 12.52 Impact Factor
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