IMMUNE RESPONSES TO LEISHMANIA INFECTION
Mice from the majority of inbred strains (C57BL/6, C3He, Sv129…) are resistant to infection by Leishmania major (L. major), an obligate intracellular protozoan parasite of macrophages in the mammalian host. In contrast, mice from BALB strains are unable to control infection and develop progressive disease. Several subsets of CD4+ T cells distinguishable by the pattern of cytokines they produce in vitro have been described. Among them, Th1 cells are characterized by secretion of IFNγ and LT, while Th2 cells produce IL-4, IL-5 and IL-13. In the murine model of infection with L. major, genetically determined resistance and susceptibility have been clearly shown to result from the appearance of parasite-specific CD4+ T helper 1 (Th1) or T helper 2 (Th2) cells, respectively. This murine model of infection is considered as one of the best experimental system for the study of the mechanisms operating in vivo at the initiation of polarized Th1 and Th2 cell maturation.
Among the several factors influencing Th cell development, cytokines themselves critically regulate this process. Using this model, it has been demonstrated that IL-12 and IL-4 promote Th1 and Th2 cell development, respectively. In addition, cross-talks between different cells at the site of infection also influence the development of a Leishmania-specific immune response.
The aim of our projects is to further investigate the immunological basis accounting for susceptibility or resistance to infection with L. major and other Leishmania species, deciphering the relative importance of different cell populations in protective immunity as well as the different mechanisms involved in T helper differentiation.
I. Role of neutrophils in the immune response to infection with Leishmania parasites
The development of a protective immune response to microorganisms involves complex interactions between the host and the pathogen. The murine model of infection with L. major allows the study of the parameters leading to the development of a protective immune response. Following infection, most strains of mice are able to heal their lesions, while a few fail to control infection, a process linked to the development of specific subsets of T helper cells, Th1 or Th2 respectively. The mechanisms leading to T helper differentiation are complex and not fully understood.
The early events occurring during the first days of parasite inoculation are thought to be critical in the development of the Leishmania-specific immune response. Neutrophils are the first cells arriving massively to the site of infection, and cumulating evidence points to their role as organizers of the immune response. In the presence of Leishmania, neutrophils from resistant strains of mice secrete distinct cytokines and chemokines influencing the microenvironment at the site of parasite inoculation (Figure 1). Transient depletion of neutrophils was shown to significantly affect the course of infection following inoculation with different Leishmania species. We are currently studying in detail how neutrophils regulate the development of Leishmania-specific immune responses, and investigating the impact of neutrophils in the early events shaping the development of the immune response.
Figure 1. L. major induces distinct phenotypes and cytokine secretion in neutrophils from mice resistant (C57BL/6) or susceptible (BALB/c) to infection.
In addition, we recently initiated a study exploring the effects of sandfly salivary gland components on the microenvironment upon parasite inoculation, and we are currently analyzing their impact on the development of Leishmania-specific immune response.
II. Role of Notch signaling in CD4+ T helper differentiation
We are studying CD4+ T helper differentiation for many years, both in vitro and in vivo, using mouse experimental models including cutaneous leishmaniasis models. Recently, we have investigated the role of Notch receptor signaling during CD4+ T helper differentiation. The protective immune response to intracellular parasites involves in most cases the differentiation of IFNγ-secreting CD4+T helper 1 cells. Notch receptors regulate cell differentiation during development but their implication in the polarization of peripheral CD4+ T helper 1 cells is not well understood. Of the four Notch receptors, only Notch1 (N1) and Notch2 (N2) are expressed on activated CD4+ T cells. To investigate the role of Notch in Th1 cell differentiation following parasite infection, mice with T cell-specific gene ablation of N1, N2 or both (N1N2ΔCD4cre) were infected with the protozoan parasite Leishmania major. N1N2ΔCD4cre mice, on the C57BL/6 L. major-resistant genetic background, developed unhealing lesions and uncontrolled parasitemia. Susceptibility correlated with impaired secretion of IFNγ by draining lymph node CD4+ T cells and increased secretion of the Th2 cytokines IL-5 and IL-. Furthermore, we showed that Notch signaling is required for the secretion of IFNγ by Th1 cells, an effect independent of CSL/RBP-Jk, the major effector of Notch receptors, since L. major-infected mice with a RBP-Jk deletion in their T cells were able to develop IFNγ-secreting Th1 cells, kill parasites and heal their lesions. We are currently pursuing these studies, investigating the role of Notch signaling in the differentiation of other CD4+ T helper subsets, using experimental models of infection with Leishmania parasites.
Collaborations. We are currently collaborating with the groups of Dr James Alexander, University of Strathclyde, Glasgow, Scotland; Dr Pascale Kropf, London School of Hygiene and Tropical Medicine, England; Drs Aldina Barral and Camilla Indiani de Oliveira, Fiocruz Institute, Bahia, Brazil; Dr Christoph Mueller, Institute of Pathology, University of Bern; Dr Freddy Radtke (ISREC/EPFL), Lausanne; Dr Robson MacDonald, Ludwig Center for Cancer Research of the UNIL; Dr Hans Acha-Orbea and Dr Sanjiv Luther Department of Biochemisty, Epalinges, UNIL.
Recent selected publications:
- Schuster S, Hurrell B, Tacchini-Cottier F. Crosstalk between neutrophils and dendritic cells: a context dependent process. 2013. J Leuk Biol. DOI: 10.1189/jlb.1012540.
- Mastelic B, Kamath AT, Fontannaz P, Tougne C, Rochat AF, Belnoue E, Combescure C, Auderset F, Lambert PH, Tacchini-Cottier F1, Siegrist CA1. 1shared senior authorship. 2012. Environmental and T cell-intrinsic factors limit the expansion of neonatal follicular T helper cells but may be circumvented by specific adjuvants. J Immunol. 2012 Dec 15;189(12):5764-72. doi: 10.4049/jimmunol.1201143. Epub 2012 Nov 16.
- Auderset F, Schuster S, Coutaz M, Koch U, Desgranges F, Merck E, MacDonald HR, Radtke F, Tacchini-Cottier F. Redundant Notch1 and Notch2 signaling is necessary for IFNγ secretion by T helper 1 cells during infection with Leishmania major. PLoS Pathog. 2012;8(3):e1002560. doi: 10.1371/journal.ppat.1002560. Epub 2012 Mar 1.
- Tacchini-Cottier F, Weinkopff T, Launois P. Does T helper differentiation correlate with resistance or susceptibility to infection with L. major? Some insights from the murine model. Front Immunol. 2012;3:32. doi: 10.3389/fimmu.2012.00032. Epub 2012 Feb 27.
- Revaz-Breton M, Ronet C, Hauyon-La Torre Y, Tacchini-Cottier F, Launois P. The MyD88 pathway is differently involved in immune responses induced by distinct substrains of Leishmania major. Eur J Immunol. 2010 Jun;40(6):1697-707. doi: 10.1002/eji.200939821.
- Charmoy M, Brunner-Agten S, Aebischer D, Auderset F, Launois P, Milon G, Proudfoot AEI, Tacchini-Cottier F. Neutrophilderived CCL3 is essential for the rapid recruitment of dendritic cells to the site of Leishmania major inoculation in resistant mice. PLoS Pathog. 2010 Feb 5;6(2):e1000755. doi: 10.1371/journal.ppat.1000755.
- Ronet C, Hauyon La Torre, Y, Revaz-Breton M, Mastelic B, Tacchini-Cottier F, Louis J, Launois P. Regulatory B cells shape the development of Th2 immune response in BALB/c mice infected with Leishmania major through IL-10 production. J Immunol. 2010 Jan 15;184(2):886-94. doi: 10.4049/jimmunol.0901114. Epub 2009 Dec 4.
- Fiorini E, Merck E, Wilson A, Ferrero I, Jiang, W, Koch U, Auderset F., Laurenti F, Pierres M, Radtke F, Luthe, S, MacDonald, HR. Dynamic regulation of Notch1 and Notch2 surface expression during T cell development and activation revealed by novel monoclonal antibodies. J Immunol. 2009 Dec 1;183(11):7212-22. doi: 10.4049/jimmunol.0902432. Epub 2009 Nov 13.
- Chakour R, Allenbach C, Desgranges F, Charmoy M, Mauel J, Garcia I, Launois P, Louis J, Tacchini-Cottier F. A new function of the Fas-FasL pathway in macrophage activation. J Leukoc Biol. 2009 Jul;86(1):81-90. doi: 10.1189/jlb.1008590. Epub 2009 Apr 20.
- Allenbach C, Launois P, Mueller C, Tacchini-Cottier F. An essential role for transmembrane TNF in the resolution of the inflammatory lesion induced by Leishmania major infection. Eur J Immunol. 2008 Mar;38(3):720-31. doi: 10.1002/eji.200737662.
- McFarlane E, Perez C, Charmoy M, Allenbach C, Carter KC, Alexander J, Tacchini-Cottier F. Neutrophils contribute to development of a protective immune response during onset of infection with Leishmania donovani. Infect Immun. 2008 Feb;76(2):532-41. Epub 2007 Dec 3.
- Charmoy M, Megnekou R, Allenbach C, Zweifel C, Perez C, Monnat K, Breton M, Ronet C, Launois P, Tacchini-Cottier F. Leishmania major induces distinct neutrophil phenotypes in mice that are resistant or susceptible to infection. J Leukoc Biol. 2007 Aug;82(2):288-99. Epub 2007 Apr 20.