Abstract
How follicular T-helper (Tfh) cells develop is incompletely understood. We find that, upon antigen exposure in vivo, both naïve and antigen-experienced T cells sequentially upregulate CXCR5 and Bcl6 within the first 24 h, relocate to the T-B border, and give rise to phenotypic Bcl6+CXCR5+ Tfh cells before the first cell division. CXCR5 upregulation is more dependent on ICOS costimulation than that of Bcl6, and early Bcl6 induction requires T-cell expression of CXCR5 and, presumably, relocation toward the follicle. This early and rapid upregulation of CXCR5 and Bcl6 depends on IL-6 produced by radiation-resistant cells. These results suggest that a Bcl6hiCXCR5hi phenotype does not automatically define a Tfh lineage but might reflect a state of antigen exposure and non-commitment to terminal effector fates and that niches in the T-B border and/or the follicle are important for optimal Bcl6 induction and maintenance.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-015-0210-0) contains supplementary material, which is available to authorized users.
Highlights
Tfh cells are functionally distinguished by their ability to deliver contact-dependent help to B cells inside the follicleXin Chen and Weiwei Ma have contributed to this work.Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.(Crotty, 2011; Vinuesa and Cyster, 2011)
Here we have examined the earliest kinetics of CXCR5 and Bcl6 expression by T cells activated in vivo and surprisingly found that T cells with a Bcl6hiCXCR5hi phenotype arise before the first cell cycle and that CXCR5 is required for optimal Bcl6 upregulation
This rapid appearance of Tfh-like cells was not a recall response of memory cells potentially contaminating our T cell preparation, because CXCR5 and Bcl6 upregulation were evident by 24 h when CD4+CD25-CD62LhighCD44low OT-II T cells were tested (Fig. 1D). It was not a peculiar behavior of naïve T cells, because OT-II T cells that were first activated in vitro rapidly and sequentially upregulated CXCR5 and Bcl6 in vivo with an essentially identical kinetics after OVA immunization (Fig. S1). These data suggest that CXCR5 and Bcl6 upregulation may be a stereotypic behavior of T cells responding to antigenic stimulation in vivo and that the appearance of a Bcl6hiCXCR5hi Tfh phenotype per se could reflect acute antigenic activation rather than a differentiation program
Summary
Tfh cells are functionally distinguished by their ability to deliver contact-dependent help to B cells inside the follicleXin Chen and Weiwei Ma have contributed to this work.Electronic supplementary material The online version of this article (doi:10.1007/s13238-015-0210-0) contains supplementary material, which is available to authorized users.(Crotty, 2011; Vinuesa and Cyster, 2011). One proposal is that Bcl drives CXCR5 upregulation, which subsequently promotes follicular localization of activated T cells. Consistent with this idea, Bcl overexpression in T cells in vitro downregulates multiple microRNA species such as the mir-17∼92 cluster that potentially suppress CXCR5 expression, leading to increased CXCR5 transcript levels (Yu et al, 2009). The Tfh developmental program is thought to follow a typical Th effector differentiation paradigm in that accessory signals delivered by DCs drives expression of fate-determining transcription factors, which orchestrate epigenetically inheritable lineage commitment through successive cell cycles (Zhu et al, 2010; Crotty, 2011). Here we have examined the earliest kinetics of CXCR5 and Bcl expression by T cells activated in vivo and surprisingly found that T cells with a Bcl6hiCXCR5hi phenotype arise before the first cell cycle and that CXCR5 is required for optimal Bcl upregulation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
