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: We first characterized steady-state MHCII expression by primary murine LNSCs. As previously described (Malhotra et al., 2012), LECs, BECs, and FRCs, but not DN cells (Fig. S1), expressed low basal levels of MHCII molecules (Fig. 1 A). MHCII expression is almost exclusively controlled by a single master regulatory factor, CIITA (Reith et al., 2005). Expression of CIITA is regulated mainly at the transcriptional level by a large regulatory region that contains three distinct promoters in mice, pI, pIII, and pIV (Fig. S2; Reith et al., 2005). We quantified pI, pIII, and pIV mRNA in FACS-sorted FRCs, BECs, and LECs from CD45neg-enriched LN fractions. Although pI and pIII mRNAs were undetectable, all three LNSC subpopulations expressed pIV mRNA (Fig. 1 B). Because pIV is induced by IFN-γ, we injected WT and pIV knockout (pIV−/−) mice with IFN-γ and observed that LECs, BECs, and FRCs isolated from WT mice strongly up-regulated MHCII compared with untreated WT mice (Fig. 1 C). In contrast, LECs, BECs and FRCs isolated from pIV−/− mice did not increase MHCII after IFN-γ treatment (Fig. 1 C), demonstrating that IFN-γ–mediated MHCII up-regulation by LNSC is pIV dependent. Surprisingly, although only pIV mRNA was detected in LNSC (Fig. 1 B), basal MHCII expression was slightly reduced but not abrogated in cells isolated from untreated pIV−/− mice. Similarly, this reduced but clear expression of MHCII was detectable in IFN-γR−/− LNSCs (Fig. 1 D), indicating that although steady-state IFN-γ is partially responsible for pIV-dependent basal MHCII expression, other mechanisms driving MHCII expression must also exist.
Affiliation: Department of Pathology and Immunology, University of Geneva Medical School, 1211 Geneva, Switzerland.