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 investigate which transcription factors are regulated by ICOS-mediated signaling and might play a role for the maintenance of the TFH phenotype, we performed a transcriptome analysis. Antigen-specific TFH cells were sorted from draining lymph nodes after 6 h of blocking ICOS-L. Comparing the ICOS-L blockade with the control group, we observed no difference for any of the transcription factors known to be important for TFH cell differentiation including Bcl-6, Blimp-1, Irf4, Ascl2, and c-Maf. However, the zinc-finger transcription factor Klf2 showed up as one of the most significantly differentially regulated genes. This transcription factor is highly expressed in naive T cells, strongly down-regulated shortly after T cell receptor triggering, and maintained on a lower level in activated T cells (Fig. 6 A). The sixfold lower expression of Klf2 in TFH versus non-TFH cells made it a particularly interesting target for further analyses (Fig. 6 B). Upon blocking ICOS-L, Klf2 was rapidly up-regulated by a factor of 3.5, approaching the expression levels of non-TFH cells (Fig. 6 C). Klf2 was originally described as a factor controlling thymocyte egress via up-regulation of sphingosine-1-phosphate receptor 1 (S1PR1) and CD62L (Carlson et al., 2006). Therefore, we analyzed these target genes on antigen-specific TFH cells after ICOS-L blockade. CD62L and S1PR1 were up-regulated 1.6- and 2.8-fold, respectively, whereas CD69, which is inversely regulated to S1PR1 (Shiow et al., 2006), was reduced by 30% (Fig. 6 D). In contrast, blockade of the CD28 pathway did not change Klf2 expression or expression of any of the latter receptors (Fig. 6 E).
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.