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