Intestinal CD103+ Dendritic Cells Are Key Players in the Innate Immune Control of Cryptosporidium parvum Infection in Neonatal Mice

et al. (2013) Intestinal CD103+ Dendritic Cells Are Key Players in the Innate Immune Control of Cryptosporidium parvum Infection in Neonatal Mice. PLoS Pathog 9(12): e1003801. doi:10.1371/journal.ppat.1003801 Intestinal CD103+ Dendritic Cells Are Key Players in the Innate Immune Control of Cryptosporidium parvum Infection in Neonatal Mice Louis Lantier 0 Sonia Lacroix-Lamande 0 Laurent Potiron 0 Coralie Metton 0 Franc oise Drouet 0 William Guesdon 0 Audrey Gnahoui-David 0 Yves Le Vern 0 Edith Deriaud 0 Aurore Fenis 0 Sylvie Rabot 0 Amandine Descamps 0 Catherine Werts 0 Fabrice Laurent 0 Dominique Soldati-Favre, University of Geneva, Switzerland 0 1 INRA, UMR1282 Infectiologie et Sante Publique, Nouzilly, France, 2 Universite Francois Rabelais, UMR1282 Infectiologie et Sante Publique, Tours, France, 3 Institut Pasteur, Unite de Re gulation Immunitaire et Vaccinologie, Paris, France, 4 Centre d'Immunologie de Marseille-Luminy, Universite d'Aix-Marseille , Marseille, France, 5 INRA, UMR 1319, Micalis, Jouy-en-Josas , France , 6 Institut Pasteur, Unite de Biologie et Ge ne tique de la Paroi Bacte rienne , Paris , France Cryptosporidium parvum is a zoonotic protozoan parasite found worldwide, that develops only in the gastrointestinal epithelium and causes profuse diarrhea. Using a mouse model of C. parvum infection, we demonstrated by conditional depletion of CD11c+ cells that these cells are essential for the control of the infection both in neonates and adults. Neonates are highly susceptible to C. parvum but the infection is self-limited, whereas adults are resistant unless immunocompromised. We investigated the contribution of DC to the age-dependent susceptibility to infection. We found that neonates presented a marked deficit in intestinal CD103+ DC during the first weeks of life, before weaning, due to weak production of chemokines by neonatal intestinal epithelial cells (IEC). Increasing the number of intestinal CD103+ DC in neonates by administering FLT3-L significantly reduced susceptibility to the infection. During infections in neonates, the clearance of the parasite was preceded by a rapid recruitment of CD103+ DC mediated by CXCR3-binding chemokines produced by IEC in response to IFNc. In addition to this key role in CD103+ DC recruitment, IFNc is known to inhibit intracellular parasite development. We demonstrated that during neonatal infection CD103+ DC produce IL-12 and IFNc in the lamina propria and the draining lymph nodes. Thus, CD103+DC are key players in the innate immune control of C. parvum infection in the intestinal epithelium. The relative paucity of CD103+ DC in the neonatal intestine contributes to the high susceptibility to intestinal infection. - Funding: This work was supported by INRA (http://www.international.inra.fr/) and by a grant from ICSA, the French Carnot Institute for Animal Health (http:// www.ic-sante-animale.org/index.php/fr/). Part of this work was also supported by the EMMA service under the EU contract Grant Agreement Number 227490 of the EC FP7 Capacities Specific Programme (http://www.emmanet.org/projects/emmaservice.php). LL and WG have PhD fellowships from INRA and the Region Centre (http://www.regioncentre.fr/accueil/les-services-en-ligne/la-region-centre-vous-aide/recherche-et-innovation/bourses-doctorales.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Cryptosporidium parvum is a waterborne protozoan parasite. It is highly prevalent worldwide affecting primarily populations in underdeveloped countries but also causes disease in industrialized countries such as the US where there are approximately 748,000 cryptosporidiosis cases annually [1]. Infection of the intestinal epithelium by this zoonotic agent results in sickness and severe diarrhea that can be life threatening in very young children and ruminants. Immunocompetent adults are relatively resistant to the infection but immunosuppressed individuals, particularly those with HIV infection, are particularly susceptible [2]. As for humans and ruminants, age-related differences in susceptibility are observed in the mouse model of infection used to study the immune mechanism leading to protection. The severity of this infection is related to the immune status of its host. Unlike other intestinal parasites, such as Toxoplasma gondii, C. parvum is only minimally invasive and its development throughout its life cycle is restricted to the epithelial layer. Therefore, in addition to its economic and clinical importance, it can serve as a model for studies of the immune mechanisms protecting the neonatal epithelium. Neonates are generally more susceptible than adults to infectious diseases [3]. Their intestinal immune system is in development and subject to numerous changes after birth, facing the colonization by the commensal flora, alimentary antigens, and aggression by enteric pathogens [3]. Both qualitative and quantitative differences between the neonatal and adult immune systems have been documented [4]. Several factors in the intestine can contribute to neonatal susceptibility to infections; they include the thinner than adult mucous layer, low level of epithelial proliferation, low alpha defensin production, and lower level of expression or specific compartmentalization of various TLRs [5]. In addition, the numbers of resident lamina propria and intraepithelial T lymphocytes are low at birth although they increase thereafter [6]. Neonatal mononuclear phagocytes have Dendritic cells are central to the defense against mucosal pathogens. They are numerous and form a uniform network in the intestinal mucosa of adults, but are poorly characterized in the intestine of neonates. Young animals are more susceptible than adults to intestinal pathogens, such as Cryptosporidium parvum, a zoonotic agent distributed worldwide that develops in the epithelium of the small intestine causing profuse diarrhea. We show that dendritic cells are scarce in the small intestine of neonates until weaning and that increasing their numbers in vivo results in increased resistance to infection. Using a conditional depletion model we demonstrate that the presence of dendritic cells is necessary for the control of the infection in both neonates and adults. During infection in neonates, dendritic cells are rapidly recruited into the intestine by chemokines produced by the epithelium and produce interferon gamma, a cytokine that inhibits parasite development in epithelial cells. Thus, the low number of dendritic cells in the intestinal mucosa of neonates is responsible for their sensitivity to cryptosporidiosis, and probably contributes to the general susceptibility of neonates to intestinal diseases. been characterized in human cord blood and in the spleen of mice [7], but much less is known about the presence of the subsets (...truncated)