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 understand the molecular mechanisms, we first quantified the expression of key molecules for TFH cell development and function at an early point in time. 3 d after immunization (similar data were obtained for days 2 and 4; not depicted), only a small fraction of CD28-deficient T cells expressed the TFH master transcription factor Bcl-6 (Fig. 2 A). Unexpectedly, we found that ICOS KO T cells up-regulated Bcl-6 to a similar extent as WT T cells, which seems to be in contrast to published data (Choi et al., 2011), as discussed below. In CD28- and ICOS-deficient T cells, the regulation of the two major TFH homing chemokine receptors was significantly impaired with an incomplete down-regulation of CCR7 and reduced up-regulation of CXCR5 (Fig. 2 A). However, when we analyzed the migration of developing TFH cells by immunohistology, ICOS-deficient T cells migrated to a similar extent as WT T cells toward the T/B cell border (Fig. 2 D). In stark contrast, CD28-deficient T cells remained equally distributed in the T cell zone. In the WT group, some T cells had already moved deeper into the B cell zone. These cells were reduced by 50% in the ICOS KO group (unpublished data), which is in line with findings by Xu et al. (2013), demonstrating that at later times (beyond day 4), a substantial difference regarding follicular localization of ICOS-deficient T cells develops.
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.