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ICOS maintains the T follicular helper cell phenotype by down-regulating Krüppel-like factor 2.

Weber JP, Fuhrmann F, Feist RK, Lahmann A, Al Baz MS, Gentz LJ, Vu Van D, Mages HW, Haftmann C, Riedel R, Grün JR, Schuh W, Kroczek RA, Radbruch A, Mashreghi MF, Hutloff A - J. Exp. Med. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Chronic Immune Reactions, Cell Biology, and Bioinformatics, German Rheumatism Research Centre, a Leibniz Institute, 10117 Berlin, Germany Molecular Immunology, Robert Koch Institute, 13353 Berlin, Germany.

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CD28 and ICOS are both important for the generation of a TFH cell population on day 8. WT (Thy-1.1+ 1.2+, black) and CD28 KO (Thy-1.1+, blue) or WT and ICOS KO (Thy-1.1+, red) OT-II T cells were co-transferred together with B1-8i B cells into C57BL/6 recipients (Thy-1.2+). Recipients were subcutaneously immunized with NP-OVA on the following day and draining lymph nodes were analyzed on day 8 after immunization by flow cytometry. (A) Representative contour plots (gated on CD4+ T cells) showing the expansion of WT and KO T cells (indicated as percentage ± SD of all CD4+ T cells). (B) Gated OT-II T cells were analyzed for a TFH phenotype defined by expression of CXCR5 and PD-1. Representative contour plots and graphs showing frequency and absolute numbers of TFH cells with dots representing individual mice and bars indicating the mean. Data are representative of four independent experiments with six animals per group. ***, P < 0.001.
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fig1: CD28 and ICOS are both important for the generation of a TFH cell population on day 8. WT (Thy-1.1+ 1.2+, black) and CD28 KO (Thy-1.1+, blue) or WT and ICOS KO (Thy-1.1+, red) OT-II T cells were co-transferred together with B1-8i B cells into C57BL/6 recipients (Thy-1.2+). Recipients were subcutaneously immunized with NP-OVA on the following day and draining lymph nodes were analyzed on day 8 after immunization by flow cytometry. (A) Representative contour plots (gated on CD4+ T cells) showing the expansion of WT and KO T cells (indicated as percentage ± SD of all CD4+ T cells). (B) Gated OT-II T cells were analyzed for a TFH phenotype defined by expression of CXCR5 and PD-1. Representative contour plots and graphs showing frequency and absolute numbers of TFH cells with dots representing individual mice and bars indicating the mean. Data are representative of four independent experiments with six animals per group. ***, P < 0.001.

Mentions: To analyze the role of CD28 and ICOS co-stimulation for different phases of TFH cell development and the GC reaction, we used an adoptive transfer mouse model with antigen-specific T and B cells from ovalbumin-specific OT-II T cell receptor transgenic and nitrophenol (NP)-specific B1-8i B cell receptor knock-in mice, respectively. Transgenic WT, KO, and recipient’s T cells within the same animal could be discriminated in flow cytometry by differential expression of congenic markers (Fig. 1 A). The double transfer of WT and KO T cells allowed for normal differentiation of GC B cells in the recipient and therefore to analyze the T cell–intrinsic effect of the respective co-stimulator deficiency. 8 d after immunization with an NP-OVA conjugate, lack of CD28 or ICOS co-stimulation resulted in a 100-fold or 25-fold reduction in the numbers of TFH cells, respectively (Fig. 1 B).


ICOS maintains the T follicular helper cell phenotype by down-regulating Krüppel-like factor 2.

Weber JP, Fuhrmann F, Feist RK, Lahmann A, Al Baz MS, Gentz LJ, Vu Van D, Mages HW, Haftmann C, Riedel R, Grün JR, Schuh W, Kroczek RA, Radbruch A, Mashreghi MF, Hutloff A - J. Exp. Med. (2015)

CD28 and ICOS are both important for the generation of a TFH cell population on day 8. WT (Thy-1.1+ 1.2+, black) and CD28 KO (Thy-1.1+, blue) or WT and ICOS KO (Thy-1.1+, red) OT-II T cells were co-transferred together with B1-8i B cells into C57BL/6 recipients (Thy-1.2+). Recipients were subcutaneously immunized with NP-OVA on the following day and draining lymph nodes were analyzed on day 8 after immunization by flow cytometry. (A) Representative contour plots (gated on CD4+ T cells) showing the expansion of WT and KO T cells (indicated as percentage ± SD of all CD4+ T cells). (B) Gated OT-II T cells were analyzed for a TFH phenotype defined by expression of CXCR5 and PD-1. Representative contour plots and graphs showing frequency and absolute numbers of TFH cells with dots representing individual mice and bars indicating the mean. Data are representative of four independent experiments with six animals per group. ***, P < 0.001.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4322049&req=5

fig1: CD28 and ICOS are both important for the generation of a TFH cell population on day 8. WT (Thy-1.1+ 1.2+, black) and CD28 KO (Thy-1.1+, blue) or WT and ICOS KO (Thy-1.1+, red) OT-II T cells were co-transferred together with B1-8i B cells into C57BL/6 recipients (Thy-1.2+). Recipients were subcutaneously immunized with NP-OVA on the following day and draining lymph nodes were analyzed on day 8 after immunization by flow cytometry. (A) Representative contour plots (gated on CD4+ T cells) showing the expansion of WT and KO T cells (indicated as percentage ± SD of all CD4+ T cells). (B) Gated OT-II T cells were analyzed for a TFH phenotype defined by expression of CXCR5 and PD-1. Representative contour plots and graphs showing frequency and absolute numbers of TFH cells with dots representing individual mice and bars indicating the mean. Data are representative of four independent experiments with six animals per group. ***, P < 0.001.
Mentions: To analyze the role of CD28 and ICOS co-stimulation for different phases of TFH cell development and the GC reaction, we used an adoptive transfer mouse model with antigen-specific T and B cells from ovalbumin-specific OT-II T cell receptor transgenic and nitrophenol (NP)-specific B1-8i B cell receptor knock-in mice, respectively. Transgenic WT, KO, and recipient’s T cells within the same animal could be discriminated in flow cytometry by differential expression of congenic markers (Fig. 1 A). The double transfer of WT and KO T cells allowed for normal differentiation of GC B cells in the recipient and therefore to analyze the T cell–intrinsic effect of the respective co-stimulator deficiency. 8 d after immunization with an NP-OVA conjugate, lack of CD28 or ICOS co-stimulation resulted in a 100-fold or 25-fold reduction in the numbers of TFH cells, respectively (Fig. 1 B).

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Chronic Immune Reactions, Cell Biology, and Bioinformatics, German Rheumatism Research Centre, a Leibniz Institute, 10117 Berlin, Germany Molecular Immunology, Robert Koch Institute, 13353 Berlin, Germany.

Show MeSH
Related in: MedlinePlus