Cross‐presenting dendritic cells are required for control of Leishmania major infection

Abstract

Keywords: Batf-3 r CD8α + dendritic cells r Leishmania majorAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe immune response to Leishmania major in mice has highlighted the relevance of Th1/Th2 cell differentiation in determining the outcome of infection in vivo. C57BL/6 mice develop self-healing lesions characterized by a Th1 cell response with high levels of IFN-γ secreted by CD4 + T cells, which activates the antimicrobial Correspondence: Prof. Hans Acha-Orbea e-mail: hans.acha-orbea@unil.chproperties of macrophages [1,2]. In contrast, BALB/c mice develop nonhealing lesions associated with Th2-and Th17-cell immune responses with high levels of IL-4, IL-5, . The adaptive immune response is largely initiated by dermal and draining lymph node (dLN)-resident DC subsets [7]. DCs are antigen-presenting cells expressing a large number of costimulatory molecules that efficiently prime T cells. Several DC subsets have been described based on their origin, phenotypic characteristics, and location [8]. However, the role of the different subsets in L. major is debated due to the varying routes of administration, strain of parasite, and dosage of parasite inoculated that C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 1422-1432 Immunity to infection 1423 have been used in the studies [4]. Inflammatory monocyte DCs (iDCs) develop at the site of infection, and upon infection, migrate to the dLNs where they present Leishmania antigens to T cells [9][10][11] Results Batf3−/− mice on a C57BL/6 background display increased susceptibility to L. major Batf3−/− mice were infected with 3 × 10 6 L. major promastigotes in the hind footpad and lesion size was monitored over several weeks. In comparison to WT C57BL/6 mice, Batf3 −/− mice developed significantly larger lesion size after 6 weeks of infection while in C57BL/6 mice, the lesions decreased thereafter (Fig. 1A). To study whether the enhanced lesion size correlated with increased parasite burden, we determined the parasite load at 3, 6, and 10 weeks postinfection. Parasite burden was significantly higher by 3 weeks and increased at 6 weeks postinfection, when significant differences in the lesion size between Batf3 −/− and C57BL/6 mice began to appear (Fig. 1B). The peak of infection at 10 weeks corresponded to the peak of parasite load as well. L. major-infected Batf3 −/− dLNs have significantly higher numbers of cells including some DC subsetsWe next assessed the composition of the dLN in L. major-infected mice at 3, 6, and 10 weeks postinfection. Mice were sacrificed at various time points and T cells, B cells, iDCs, CD11b + , CD8α + as well as plasmacytoid DCs (pDCs) were identified using the gating strategy depicted in Fig. 2A. Infected Batf3 −/− mice had significantly higher absolute number of dLN cells at 6 and 10 weeks postinfection ( Fig. 2B), a feature also observed in L. majorsusceptible BALB/c mice (data not shown). Since differences in...

Leishmania, the phagosome, and host responses: The journey of a parasite

“…IFN- was also shown to be mainly produced by the crosspresenting DC subset compared to the CD103 DC subset. Furthermore, Balf3 deletion and cross-presenting DC depletion during infection led to the similar increases in wound size and parasite load [72].…”

Timing is everything: dendritic cell subsets in murine Leishmania infection

“…Recent studies have, therefore, highlighted the role for both inflammatory moDCs and the cross-presenting DC subsets towards a protective immune response to L. major [47,69]. We propose that a collaboration could exist between the inflammatory moDC and the CD8 + DCs, since moDCs efficiently transfer peptide/MHC complexes to CD8 + DCs for presentation (cross-dressing) during viral infection [73], so it is possible that such a process also occurs during Leishmania infection.…”

“…Due to the absence of the transcription factor basic leucine zipper transcription factor ATFlike 3 (BATF3), these mice lack both CD8 + and CD103 + DC subsets, but show a normal distribution of other DC including moDC [70]. These mice become highly susceptible to L. major infection, develop exacerbated lesions compared to resistant wild type C57BL/6 mice, and the lesion size remains higher even at a later time of infection (i.e., after 15-16 weeks) [69]. The same applies to the low dose injection model.…”

“…Recently, however, the important role of CD8 + and CD103 + DCs in protection from L. major infection using batf3 À/À mice was described [69]. Three weeks after infection, CD8 + but not CD103 + DC could present antigen ex vivo to primed Leishmania-specific T cells.…”

A sinalização via NOD2-RIP2 modula a imunidade adaptativa contra <i>Leishmania infantum</i>

“…Priming and maintenance of effectors T cells against Leishmania involve well-regulated actions of different DC subsets [25]. Basic leucin zipper transcription factor, ATF-like 3 (Batf3) -dependent CD8α + XCR1 + DCs in addition to be specialized in cross presentation, is the major source of IL-12 in L. major infection, been crucial for Th1 immunity but dispensable for Th2 and Th17 [26,27]. In the present study, we have focused on the mechanisms underlying the triggering of the NOD2-RIP2 pathway in modulating the protective immune response against L. infantum infection.…”