SHP-1 Regulates Antigen Cross-Presentation and Is Exploited by Leishmania to Evade Immunity

• Published in: Cell reports (Cambridge) Vol. 33; no. 9; p. 108468
• Main Authors: Khouili, Sofía C., Cook, Emma C.L., Hernández-García, Elena, Martínez-López, María, Conde-Garrosa, Ruth, Iborra, Salvador
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2020; Elsevier
• Subjects: Animals; antigen cross-presentation; Antigen Presentation - immunology; Clec4e; Cross-Priming - immunology; dendritic cells; immune evasion; Leishmania; Mice; Mincle; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism; Ptpn6; SHP-1; sialic acid; vaccines; dendritic cells; immune evasion; sialic acid; vaccines; Leishmania; Ptpn6; Mincle; SHP-1; Clec4e; antigen cross-presentation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108468

Intracellular pathogens have evolved strategies to evade detection by cytotoxic CD8+ T lymphocytes (CTLs). Here, we ask whether Leishmania parasites trigger the SHP-1-FcRγ chain inhibitory axis to dampen antigen cross-presentation in dendritic cells expressing the C-type lectin receptor Mincle. We find increased cross-priming of CTLs in Leishmania-infected mice deficient for Mincle or with a selective loss of SHP-1 in CD11c+ cells. The latter also shows improved cross-presentation of cell-associated viral antigens. CTL activation in vitro reveals increased MHC class I-peptide complex expression in Mincle- or SHP-1-deficient CD11c+ cells. Neuraminidase treatment also boosts cross-presentation, suggesting that Leishmania triggers SHP-1-associated sialic-acid-binding receptors. Mechanistically, enhanced antigen processing correlates with reduced endosomal acidification in the absence of SHP-1. Finally, we demonstrate that SHP-1 inhibition improves CD11c+ cell-based vaccination against the parasite. Thus, SHP-1-mediated impairment of cross-presentation can be exploited by pathogens to evade CTLs, and SHP-1 inhibition improves CTL responses during vaccination. [Display omitted] •Lack of Mincle or SHP-1 loss in CD11c+ cells raises CD8+ T cell priming to Leishmania•SHP-1 deficiency increases endosomal pH and enhances antigen cross-presentation•SHP-1 inhibition boosts CD11c+ cell-based vaccination efficacy against Leishmania Khouili et al. identify SHP-1 as a negative regulator of antigen cross-presentation that Leishmania can trigger by interacting with Mincle and sialic-acid-binding receptors, dampening early CD8+ T cell recognition. Loss of functional SHP-1 in CD11c+ cells decreases endosomal acidification, increases cross-presentation, and boosts CD11c+ cell-based vaccination against Leishmania.