Lymph node stromal cells acquire peptide-MHCII complexes from dendritic cells and induce antigen-specific CD4⁺ T cell tolerance.
Bottom Line: Although LNSCs express MHCII, it is unknown whether they can also impact CD4(+) T cell functions.We show that the promoter IV (pIV) of class II transactivator (CIITA), the master regulator of MHCII expression, controls endogenous MHCII expression by LNSCs.Our data reveals a novel, alternative mechanism where LN-resident stromal cells tolerize CD4(+) T cells through the presentation of self-antigens via transferred peptide-MHCII complexes of DC origin.
Affiliation: Department of Pathology and Immunology, University of Geneva Medical School, 1211 Geneva, Switzerland.Show MeSH
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Mentions: To further investigate the inhibitory capacity of LNSCs, T cells were harvested and restimulated using anti-CD3/CD28 antibodies after 3 d of culture. OT-II cells that were not exposed to any other cells noticeably proliferated upon CD3/CD28 stimulation (Fig. 8 A), as observed for T cells exposed for 3 d to WT DCs. However, OT-II cells exposed to WT LECs responded less efficiently to restimulation compared with unexposed T cells, confirming that LNSCs suppress T cell proliferation independently of the presentation of pMHC complexes (Khan et al., 2011; Lukacs-Kornek et al., 2011; Siegert et al., 2011). Ex vivo, LECs appeared to be more efficient compared with BECs and FRCs at inhibiting T cell proliferation independently of antigen presentation (Fig. 8 A). Importantly, the proliferation of T cells preexposed to CD11cDOG LECs, BECs, and FRCs was further reduced compared with T cells preexposed to WT LECs, BECs, and FRCs (Fig. 8 A). We did not observe any differences in T reg cell frequency, whether T cells were precultured alone or with LNSNs derived from WT or CD11cDOG mice (unpublished data). To firmly demonstrate that pMHCII complexes are transferred from DCs to LNSC in vivo, and to rule out that free OVA released from CD11cDOG DCs is captured and presented via endogenous MHCII expressed at the surface of LNSCs, experiments were repeated using BM chimeric mice in which LNSCs do not express endogenous MHCII. CD11cDOG BM cells were used to reconstitute irradiated CIITA−/− recipient mice. Using this setting, we confirmed that LECs, BECs, and FRCs isolated from CD11cDOG:CIITA−/− mice inhibit T cell proliferation in an antigen-specific manner compared with LNSCs isolated from WT:WT mice (Fig. 8 B). Altogether, our data demonstrated that LNSCs acquired OVA323-339–MHCII complexes from DCs in vivo, and induced an antigen-specific inhibition of OT-II survival and proliferation.
Affiliation: Department of Pathology and Immunology, University of Geneva Medical School, 1211 Geneva, Switzerland.