title: Cathepsin B-Deficient Mice Resolve Leishmania major Inflammation Faster in a T Cell-Dependent Manner.
abstract: A critical role for intracellular TLR9 has been described in recognition and host resistance to Leishmania parasites. As TLR9 requires endolysosomal proteolytic cleavage to achieve signaling functionality, we investigated the contribution of different proteases like asparagine endopeptidase (AEP) or cysteine protease cathepsins B (CatB), L (CatL) and S (CatS) to host resistance during Leishmania major (L. major) infection in C57BL/6 (WT) mice and whether they would impact on TLR9 signaling. Unlike TLR9-/-, which are more susceptible to infection, AEP-/-, CatL-/- and CatS-/- mice are as resistant to L. major infection as WT mice, suggesting that these proteases are not individually involved in TLR9 processing. Interestingly, we observed that CatB-/- mice resolve L. major lesions significantly faster than WT mice, however we did not find evidence for an involvement of CatB on either TLR9-dependent or independent cytokine responses of dendritic cells and macrophages or in the innate immune response to L. major infection. We also found no difference in antigen presenting capacity. We observed a more precocious development of T helper 1 responses accompanied by a faster decline of inflammation, resulting in resolution of footpad inflammation, reduced IFNγ levels and decreased parasite burden. Adoptive transfer experiments into alymphoid RAG2-/-γc-/- mice allowed us to identify CD3+ T cells as responsible for the immune advantage of CatB-/- mice towards L. major. In vitro data confirmed the T cell intrinsic differences between CatB-/- mice and WT. Our study brings forth a yet unappreciated role for CatB in regulating T cell responses during L. major infection.
authors.affiliation: Institut Pasteur, Département Infection et Epidémiologie, Unité Cytokines & Inflammation, Paris, France.
authors.forename: Orhan
authors.identifier: 0000-0002-7040-9587
authors.initials: O
authors.lastname: Rasid
authors.affiliation: Institut Pasteur, Département Infection et Epidémiologie, Unité Cytokines & Inflammation, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Mériaux
authors.affiliation: Institut Pasteur, Département Infection et Epidémiologie, Unité Cytokines & Inflammation, Paris, France.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Khan
authors.affiliation: Institut Pasteur, Département Infection et Epidémiologie, Unité Cytokines & Inflammation, Paris, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Borde
authors.affiliation: Institut Pasteur, Département Infection et Epidémiologie, Unité Cytokines & Inflammation, Paris, France.|Cantacuzino National Research Institute, Bucharest, Romania.
authors.forename: Ioana S
authors.initials: IS
authors.lastname: Ciulean
authors.affiliation: Institut Pasteur, Département Infection et Epidémiologie, Unité Cytokines & Inflammation, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fitting
authors.affiliation: Institut Necker Enfants Malades, INSERM U1151-CNRS UMR 8253, Hôpital Necker-Enfants Malades, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Manoury
authors.affiliation: Institut Pasteur, Département Infection et Epidémiologie, Unité Cytokines & Inflammation, Paris, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Cavaillon
authors.affiliation: Institut Pasteur, Département Infection et Epidémiologie, Unité Cytokines & Inflammation, Paris, France.
authors.forename: Noëlle
authors.initials: N
authors.lastname: Doyen
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D017252:CD3 Complex / Q000032:analysis / Q000276:immunology; D002401:Cathepsin B / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D056668:Cathepsin L / Q000172:deficiency / Q000235:genetics; D002403:Cathepsins / Q000172:deficiency / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology; D010450:Endopeptidases / Q000172:deficiency; D005528:Foot; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059208:Parasite Load; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D017252:CD3 Complex; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D007371:Interferon-gamma; D002403:Cathepsins; D010450:Endopeptidases; D002401:Cathepsin B; C533915:Ctsb protein, mouse; D056668:Cathepsin L; C534278:Ctsl protein, mouse; C028217:cathepsin S