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

ABSTRACT 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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    • "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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    • "TFH cells depend on expression of the master regulator transcription factor Bcl6. Distinguishing features of TFH cells are the expression of CXCR5, PD-1, IL-21, and ICOS, among other molecules, and the absence of Blimp-1. ICOS signaling is important for the maintenance and/or generation of TFH cells [21, 22] and reinforcing the association between ICOS expression and IL-10 production. PD-1 is induced by sustained TCR signaling and might act as a negative regulator of CD4+ T-cell proliferation. "
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    ABSTRACT: Background: T follicular helper (TFH) cells are involved in the humoral immune responses. This study is aimed at examining the frequencies of different subsets of CD4(+)CXCR5(+) TFH cells in adult patients with minimal change disease (MCD). Methods: A total of 27 patients and 14 healthy controls (HC) were characterized for the levels of sera cytokines, inducible T-cell costimulator (ICOS), and programmed death 1 (PD-1) of positive TFH cells by flow cytometry. The level of sera IL-21 was examined; 24 h urinary protein and eGFR were calculated. The potential correlation between the frequency of different subsets of TFH cells and the values of clinical measures in MCD patients were analyzed. Results: The frequency of circulating CD4(+)CXCR5(+), CD4(+)CXCR5(+)ICOS(+), and CD4(+)CXCR5(+)PD-1(+) TFH cells and the levels of sera IL-17A, IFN-γ, IL-2, IL-10, IL-4, and IL-21 were significantly higher in MCD patients (P < 0.05) than that in the HC group. Furthermore, the percentages of circulating CD4(+)CXCR5(+) TFH cells were negatively correlated with the values of eGFR (r = -0.4849, P < 0.05) and the percentages of CD4(+)CXCR5(+)PD-1(+) TFH cells were correlated positively with the levels of serum IL-21 (r = 0.6137, P < 0.05) and 24 h urinary protein (r = 0.1410, P < 0.05) in those patients. Also, the percentages of CD4(+)CXCR5(+)ICOS(+) TFH cells were correlated positively with the levels of serum IL-21 (r = 0.6201, P < 0.05) and 24 h urinary protein (r = 0.7519, P < 0.05). Following standard therapies, the percentages of circulating CD4(+)CXCR5(+), CD4(+)CXCR5(+)PD-1(+), and CD4(+)CXCR5(+)ICOS(+) TFH cells and the levels of serum IL-21 were significantly reduced, but the levels of serum IL-4 and IL-10 were increased (P < 0.05). Conclusions: A higher frequency of CD4(+)CXCR5(+) TFH cells that existed in adult patients with MCD could be new target for intervention of MCD.
    BioMed Research International 08/2014; 2014:836157. DOI:10.1155/2014/836157 · 2.71 Impact Factor
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    • "ICOS seems to play a central role in the B cell help function of CD4 T cells by providing essential signals for the initiation and maintenance of antibodies production. ICOS deficiency is associated with the loss or a defective formation of germinal centers in mice and humans [26], [27]. Recently, ICOS was shown to be required for the early differentiation of TFH cells during mouse LCMV infection [28]. "
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    ABSTRACT: The generation of high-affinity antibodies and the development of B cell memory are dependent on the help provided by CD4 T cells. Mouse studies indicate that STAT3 signaling in CD4 T cells promotes the acquisition of the B cell help function. However, the role of STAT3 in humans has been controversial. In this study, we show that IL-6 and other STAT3 activating cytokines (IL-21 and IL-27) induce the differentiation of CD4 T cells promoting antibody production by B cells. The acquisition of B cell stimulating properties by naive cord blood CD4 T cells required the STAT3-dependent expression of ICOS and IL-21. Gene reporter and ChIP experiments unambiguously demonstrated that upon IL-6 stimulation, STAT3 induces the transcription of the ICOS gene through direct recruitment to the proximal promoter region indicating that STAT3 acts in part through the direct activation of the ICOS gene.
    PLoS ONE 07/2013; 8(7):e71029. DOI:10.1371/journal.pone.0071029 · 3.23 Impact Factor
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