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
Related in: MedlinePlus
License 1 - License 2
Mentions: To test whether suppression of Klf2 is the major mechanism by which ICOS regulates TFH cell differentiation, we overexpressed Klf2 in antigen-specific T cells. OT-II T cells were retrovirally transduced with a vector coding for Klf2 and GFP or a control vector with GFP only. 1 d after infection, overexpression of Klf2 in vitro resulted in a 1.7- and 2.5-fold increased expression of its known target genes CD62L and S1pr1, respectively (Fig. 8 A). At the same time, expression levels of CD44 and other activation markers, like OX-40 and 4-1BB, were unaltered or even increased, which shows that overexpression of Klf2 did not result in a general block of T cell activation. Importantly, Bcl-6, c-Maf, Prdm1, and Ascl2 were expressed equally in both groups, demonstrating that overexpression of Klf2 did not directly regulate key factors of TFH cell differentiation. To substantiate these results, we stimulated T cells from inducible Klf2 KO mice. As expected, Klf2 mRNA and the known downstream target S1pr1 were strongly reduced, whereas expression of the TFH-related transcription factors Bcl-6, c-Maf, and Ascl-2 remained unchanged (Fig. 8 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.