Abstract
ABSTRACTIn adaptive immunity, CLEC-2+ dendritic cells (DCs) contact fibroblastic reticular cells (FRCs) inhibiting podoplanin-dependent actomyosin contractility, permitting FRC spreading and lymph node expansion. The molecular mechanisms controlling lymph node remodelling are incompletely understood. We asked how podoplanin is regulated on FRCs in the early phase of lymph node expansion, and which other proteins are required for the FRC response to DCs. We find that podoplanin and its partner proteins CD44 and CD9 are differentially expressed by specific lymph node stromal populations in vivo, and their expression in FRCs is coregulated by CLEC-2 (encoded by CLEC1B). Both CD44 and CD9 suppress podoplanin-dependent contractility. We find that beyond contractility, podoplanin is required for FRC polarity and alignment. Independently of podoplanin, CD44 and CD9 affect FRC–FRC interactions. Furthermore, our data show that remodelling of the FRC cytoskeleton in response to DCs is a two-step process requiring podoplanin partner proteins CD44 and CD9. Firstly, CLEC-2 and podoplanin binding inhibits FRC contractility, and, secondly, FRCs form protrusions and spread, which requires both CD44 and CD9. Together, we show a multi-faceted FRC response to DCs, which requires CD44 and CD9 in addition to podoplanin.
Highlights
Increased expression of podoplanin and CD44 on T-cell zone FRCs (TRCs) during adaptive immune responses It is known that fibroblastic reticular cells (FRCs) numbers remain constant in the first acute phase of lymph node expansion, and that FRC proliferation is induced later during tissue remodelling (Acton et al, 2014; Astarita et al, 2015; Yang et al, 2014)
We compared the response of lymphatic endothelial cells (LECs; CD31+PDPN+MAdCAM-1−), marginal reticular cells (MRCs; CD31−PDPN+MAdCAM-1+) and T-cell zone FRCs (TRCs; CD31−PDPN+MAdCAM-1−) through the acute phase of lymph node expansion (Fig. 1D)
The increased podoplanin expression on FRCs upon immunization is counterintuitive, since podoplanin drives FRC contractility, which is inhibited during this early phase of lymph node expansion by CLEC-2+ dendritic cells (DCs)
Summary
During the adaptive immune response, the lymph node rapidly expands to accommodate the increased number of proliferating lymphocytes (Acton et al, 2014; Astarita et al, 2015; Yang et al, 2014). Migratory dendritic cells (DCs), expressing the C-type lectin-like receptor CLEC-2 (encoded by CLEC1B), are required to initiate FRC network remodelling (Acton et al, 2014; Astarita et al, 2015). When CLEC-2 expression is deleted in DCs, lymph nodes fail to expand relative to controls and the FRC network becomes disrupted (Acton et al, 2014; Astarita et al, 2015). The molecular role of podoplanin on FRCs, and its requirement for FRCs to respond to CLEC-2+ migratory DCs, is incompletely understood
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.
