Antigen presentation, autoimmune diseases, peripheral T-cell tolerance

Our lab has a long-standing interest in the fields of anti-tumor immunity and T cell tolerance, with a particular focus on the contribution of dendritic cells (DCs) and stromal cells (SCs). Few years ago, the lab became interested in how SCs impact peripheral T cell responses. In T cell tolerance, our work shows that SCs function as antigen-presenting cells to inhibit autoimmune T cell responses and dampen autoimmunity. We demonstrated that MHCII expression by SCs results from both endogenous molecules and MHCII-peptide complexes acquired from DCs. SCs can further present DC-derived complexes to CD4+ T cells to induce their dysfunction (Dubrot et al. 2014). Furthermore, the genetic abrogation of endogenous MHCII in SCs induces the development of signs of T cell-mediated autoimmunity in aging mice (Dubrot et al. 2018). Ongoing projects performed in mouse models of autoimmune diseases (Collagen-induced Arthritis, Experimental Autoimmune Encephalomyelitis) indicate that the autophagy pathway contributes to the ability of SCs to present self-antigens through MHCII molecules to promote regulatory T cells and inhibit self-reactive pathogenic T cells (Harlé et al., submitted; Kowalski et al., in preparation). In the context of tumor, we suggest that SCs, and in particular the lymphatic endothelium in the local microenvironment may be a novel target for immunomodulation. We introduced a tumor-promoting role for lymphatic vessels by showing that the lymphangiogenic growth factor VEGF-C produced in the tumor promoted immunological tolerance in murine melanoma (Lund et al., 2012). Finally, our unpublished results show that tumor-associated lymphatic endothelial cells can function as MHCII-restricted antigen–presenting cells to maintain the suppressive phenotype of intratumoral Tregs (Gkountidi et al., submitted).

Specific expertise

We have expertise with several tumor mouse models, anti-tumor immunity and tumor vaccination protocols (Lund et al, Cell Reprots 2012, Guery et al, Cancer Research 2014, Humbert et al, Cancer Research 2018), as well as mouse models of autoimmune disease, EAE (Lippens, J Autoimmunity 2016; Duraes, J Autoimmunity 2015) and Collagen-induced arthritis.

Selected publications

Lymphatic endothelial cells educate naïve CD8+ T cells under steady-state conditions to promote a memory-like phenotype. Vokali E, Yu S, Hirosue S, Rincon-Restrepo M, Duraes F, Scherer S, Corthésy-Henrioud P, Mondino A, Zehn D, Hugues S, Swartz MA. Nat Comm, 2020 Jan 27;11(1):538

Absence of MHC-II expression by lymph node stromal cells results in autoimmunity. Dubrot J, Duraes FV, Harlé G, Schlaeppi A, Brighouse D, Madelon N, Göpfert C, Stokar-Regenscheit N, Acha-Orbea H, Reith W, Gannagé M, Hugues S. Life Sci Alliance. 2018 Dec 17;1(6)

Intratumoral CpG-B Promotes Antitumoral Neutrophil, cDC, and T-cell Cooperation without Reprograming Tolerogenic pDC. Humbert M, Guery L, Brighouse D, Lemeille S, Hugues S. Cancer Res. 2018 Jun 15;78(12):3280-3292. doi: 10.1158/0008-5472.CAN-17-2549

IDO-orchestrated crosstalk between pDCs and Tregs inhibits Autoimmunity. Lippens C., Duraes F., Dubrot J., Brighouse D., Lacroix M., Irla M., Aubry-Lachainaye J-P., Reith W., Mandl J., and Hugues S. Journal of Autoimmunity, 2016 Dec;75:39-49

Lymph node stromal cells acquire peptide-MHCII complexes from dendritic cells and induce antigen-specific CD4+ T cell tolerance. Dubrot J*, Duraes F*, Potin L, Capotosti F, Brighouse D, Suter T, LeibundGut-Landmann S, Garbi N, Reith W., Swartz MA and Hugues S. J Exp Med. 2014 Jun 2;211(6):1153-66

28 Oct 2020