Original ResearchBasic and Translational—Alimentary TractPreferential Expression of Integrin αvβ8 Promotes Generation of Regulatory T Cells by Mouse CD103+ Dendritic Cells
Section snippets
Mice
αv-tie2 mice12, 13 backcrossed to BALB/c or C57BL/6 backgrounds (10 generations) were used. FoxP3 eGFP reporter mice were obtained from Vijay Kuchroo (Brigham and Women's Hospital, Boston, MA)8 and DO11.10 mice from the Jackson Laboratory (Bar Harbor, ME). All animals were housed under specific pathogen-free conditions at Massachusetts General Hospital. Animal experiments were performed under appropriate licenses within local and national guidelines for animal care.
In Vitro Treg Generation Assay
CD4+ T cells were sorted by
CD103+ MLN DCs Activate Latent TGF-β to Generate FoxP3+ Tregs
In agreement with previous studies,10, 11 we found that CD103+ DCs from mouse MLNs generated on average twice as many FoxP3+ T cells in in vitro coculture than their CD103− counterparts (Figure 1A). This was dependent on TGF-β because TGF-β blocking antibodies completely prevented Treg generation by both CD103+ and CD103− DCs (Figure 1A). Induction of FoxP3 was also significantly impaired when DCs and T cells were cultured in serum-free medium (Figure 1B and C), despite comparable T-cell
Discussion
A specific population of intestinal DCs, marked by expression of CD103, is emerging as important regulators of intestinal immunity through their ability to promote conversion of naïve T cells to FoxP3+ Tregs that home to the intestine. Here we present data showing that the increased ability of CD103+ DCs to generate Tregs both in vitro and in vivo is completely dependent on the expression of αv integrins. This is due to an increased ability of CD103+ DCs to activate latent TGF-β, and CD103+ DCs
Acknowledgments
The authors thank Joseph McCarty (MD Anderson Cancer Center, Houston, TX) for the kind gift of antibodies to β8 integrin, J. Rodrigo Mora and Scott Snapper (Massachusetts General Hospital) for helpful discussion as well as members of the Mora and Snapper laboratories for technical advice and reagents, and David Dombkowski (Massachusetts General Hospital) for FACS.
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2020, Cellular ImmunologyApoptotic Cell–Directed Resolution of Lung Inflammation Requires Myeloid αv Integrin–Mediated Induction of Regulatory T Lymphocytes
2020, American Journal of PathologyCitation Excerpt :In the presence of gut microbiota, such mice developed spontaneous gut inflammation associated with diminished clearance of apoptotic cells, a marked reduction in Tregs in draining lymph nodes, and similarly impaired capacity of CD11c+ DCs isolated from such lymph nodes to induce FoxP3 Tregs ex vivo. We inferred that expression of αv by CD103+ DCs is necessary for αvβ5-mediated ingestion of apoptotic cells and subsequent αvβ8-mediated activation of TGF-β1 needed to induce regulatory T cells in the gut,11 a proposal supported by our subsequent work18,20 and by the work of Blander’s group.31,32 However, it was not known if such myeloid αv-dependent mechanisms operated in the lung, although Desch et al35 had demonstrated in a system geared to presentation of apoptotic cell-derived antigen to CD8 T cells that intranasally administered apoptotic cells were preferentially cleared by CD103+ DCs.
Conflicts of interest The authors disclose no conflicts.
Funding Supported by grants from the Crohn's and Colitis Foundation of America and the Hood Pediatric Research Foundation (to A.L.-H.), the National Institutes of Health (grant RO1AI79198 to L.M.S.), the UK Medical Research Council (grant G0802069 to J.S.), a Wellcome Trust traveling fellowship (to S.M.), and the Philippe Foundation and the Bettencourt-Schueller Foundation (Young Scientist Award to H.P.).