Viruses, bacteria and parasites: infection of the male genital tract and fertility.

BACKGROUND: Infertility affects one couple out of six worldwide. Male infertilty can result from congenital or acquired factors, of which pathogens that reach the genital tract through sexual contact or blood dissemination. The impact of major viral, bacterial and parasitic infections on the male genital tract and fertility has been summarized. RESULTS AND CONCLUSIONS: A systematic review of articles published in the Google Scholar and PubMed databases was conducted. It turns out that viruses, as well as bacteria and parasites are major inducers of male genital tract infections and ensuing infertility through damage to the organs and subsequent loss of function and/or through direct damage to the sperm cells. Moreover, not only male infertility results from such infections but these can also be transmitted to women and even to the offspring, thus highlighting the need to efficiently detect, treat and prevent them.

RéSUMé: CONTEXTE: L'infertilité affecte un couple sur six dans le monde. L'infertilité masculine peut être due à des facteurs congénitaux ou acquis, parmi lesquels des pathogènes qui atteignent le tractus génital par contact sexuel ou dissémination par voie sanguine. Cette revue présente les principaux pathogènes d'origine virale, bactérienne et parasitaire qui affectent le tractus génital masculin et leur impact sur la fertilité. RéSULTATS ET CONCLUSION: Une revue systématique de la littérature a été conduite à partir de Google Scholar et de PubMed. Il apparaît que les virus, au même titre que les bactéries ou les parasites, sont des facteurs majeurs d'infection du tractus génital masculin et d'infertilité. Cette dernière découle de dommages aux organes reproducteurs et à leur perte de fonction et/ou d'atteintes directes aux spermatozoïdes. De plus, ces infections n'impactent pas seulement la fertilité masculine, mais elles peuvent également être transmises aux partenaires féminines et même à la descendance, ce qui souligne l'importance de les détecter, de les traiter et de les prévenir efficacement.

Three-dimensional imaging of vascular development in the mouse epididymis.

Long considered an accessory tubule of the male reproductive system, the epididymis is proving to be a key determinant of male fertility. In addition to its secretory role in ensuring functional maturation and survival of spermatozoa, the epididymis has a complex immune function. Indeed, it must manage both peripheral tolerance to sperm antigens foreign to the immune system and the protection of spermatozoa as well as the organ itself against pathogens ascending the epididymal tubule. Although our knowledge of the immunobiology of this organ is beginning to accumulate at the molecular and cellular levels, the organization of blood and lymphatic networks of this tissue, important players in the immune response, remains largely unknown. In the present report, we have taken advantage of a VEGFR3:YFP transgenic mouse model. Using high-resolution three-dimensional (3D) imaging and organ clearing coupled with multiplex immunodetections of lymphatic (LYVE1, PDPN, PROX1) and/or blood (PLVAP/Meca32) markers, we provide a simultaneous deep 3D view of the lymphatic and blood epididymal vasculature in the mature adult mouse as well as during postnatal development.

Spermatozoa isolation with Felix™ outperforms conventional density gradient centrifugation preparation in selecting cells with low DNA damage.

BACKGROUND: The optimization of spermatozoa preparation techniques in order to obtain cell fractions enriched with structurally and functionally "superior" spermatozoa is a key objective of the assisted reproduction industry. OBJECTIVES: The purpose of this study was to evaluate a recent development of an electrophoretic spermatozoa separation device (Felix™, Memphasys Ltd, Sydney, Australia) and to compare its performance with conventional spermatozoa preparation by density gradient centrifugation (DGC). Particular attention was paid to the evaluation of sperm DNA/nuclear integrity. MATERIALS & METHODS: A cohort of 29 human semen samples was studied. Semen samples were analyzed fresh and after DGC or Felix™ preparation. Semen parameters monitored included sample volume, sperm count, total motility, progressive motility, sperm DNA fragmentation using the Sperm Chromatin Structure Assay and sperm DNA oxidation. RESULTS: Spermatozoa preparation with Felix™ resulted in significantly improved spermatozoa fractions with higher progressive motility, lower sperm DNA fragmentation, and lower sperm DNA oxidation compared with raw semen and DGC-prepared spermatozoa. DISCUSSION & CONCLUSION: The data collected in this study support the preparation of spermatozoa by the Felix™ system as it allows selection of spermatozoa with the highest progressive motility as well as the lowest nuclear/DNA damage. These improved sperm parameters, along with the fact that the Felix™ separation process is very fast and highly standardized, should be of great interest to the assisted reproduction technologies industry.

Sexually dimorphic activation of innate antitumor immunity prevents adrenocortical carcinoma development.

Unlike most cancers, adrenocortical carcinomas (ACCs) are more frequent in women than in men, but the underlying mechanisms of this sexual dimorphism remain elusive. Here, we show that inactivation of Znrf3 in the mouse adrenal cortex, recapitulating the most frequent alteration in ACC patients, is associated with sexually dimorphic tumor progression. Although female knockouts develop metastatic carcinomas at 18 months, adrenal hyperplasia regresses in male knockouts. This male-specific phenotype is associated with androgen-dependent induction of senescence, recruitment, and differentiation of highly phagocytic macrophages that clear out senescent cells. In contrast, in females, macrophage recruitment is delayed and dampened, which allows for aggressive tumor progression. Consistently, analysis of TCGA-ACC data shows that phagocytic macrophages are more prominent in men and are associated with better prognosis. Together, these data show that phagocytic macrophages are key players in the sexual dimorphism of ACC that could be previously unidentified allies in the fight against this devastating cancer.

Identification of Arvicola terrestris scherman Sperm Antigens for Immune Contraceptive Purposes.

The cyclical proliferation of the wild fossorial rodent Arvicola terrestris scherman (ATS) is critical in mid-mountain ecosystems of several European countries. Our goal is to develop an immunocontraceptive vaccine to control their fertility, as a sustainable alternative to chemical poisons currently used. Indeed, these chemicals cause the death of ATS predators and animals sharing their ecosystem, and current laws progressively limit their use, making the development of a targeted vaccination strategy an interesting and efficient alternative. In order to identify species-specific sperm antigens, male and female ATS received subcutaneous injections of whole ATS spermatozoa to elicit an immune response. The analysis of the immune sera led to the identification of 120 immunogenic proteins of sperm cells. Of these, 15 were strictly sperm-specific and located in different regions of the male gamete. Some of these antigens are proteins involved in molecular events essential to the reproductive process, such as sperm-egg interaction, acrosomal reaction, or sperm motility. This approach not only identified a panel of immunogenic proteins from ATS sperm cells, but also demonstrated that some of these proteins trigger an immune response in both male and female ATS. These spermatic antigens are good candidates for the development of a contraceptive vaccine.

Absence of nuclear receptors LXRs impairs immune response to androgen deprivation and leads to prostate neoplasia.

Chronic inflammation is now a well-known precursor for cancer development. Infectious prostatitis are the most common causes of prostate inflammation, but emerging evidence points the role of metabolic disorders as a potential source of cancer-related inflammation. Although the widely used treatment for prostate cancer based on androgen deprivation therapy (ADT) effectively decreases tumor size, it also causes profound alterations in immune tumor microenvironment within the prostate. Here, we demonstrate that prostates of a mouse model invalidated for nuclear receptors liver X receptors (LXRs), crucial lipid metabolism and inflammation integrators, respond in an unexpected way to androgen deprivation. Indeed, we observed profound alterations in immune cells composition, which was associated with chronic inflammation of the prostate. This was explained by the recruitment of phagocytosis-deficient macrophages leading to aberrant hyporesponse to castration. This phenotypic alteration was sufficient to allow prostatic neoplasia. Altogether, these data suggest that ADT and inflammation resulting from metabolic alterations interact to promote aberrant proliferation of epithelial prostate cells and development of neoplasia. This raises the question of the benefit of ADT for patients with metabolic disorders.

Differential expression and localisation of TGF-ß isoforms and receptors in the murine epididymis.

Testes produce spermatozoa that transit through and are stored in the epididymis where they acquire their fertilising capacities. Spermatozoa appear in the genital tract at puberty, long after the immune system was trained to self-antigens. As a consequence, this organ has to set strategies to tolerate sperm antigens to avoid autoimmune responses that would specifically target and destroy them. A recent study pointed the Transforming Growth Factor-beta (TGF-ß) signalling in the dendritic cells as a crucial mechanism for epididymal tolerance to spermatozoa. In the mouse, TGF-ß exists under three isoforms, and three distinct receptors have been described. Using RT-qPCR, immunohistochemistry and ELISA techniques, we investigated the expression and spatial distribution of the epididymal TGF-ß isoforms and of their receptors in young and adult mice. We showed that both ligands and receptors were produced by immune and non-immune cells in the epididymis, whatever the age mice have. These data bring new clues as to the mechanisms of peripheral tolerance to sperm cells in the murine epididymis and raise potential other implications of the cytokine isoforms.

The epididymal immune balance: a key to preserving male fertility.

Up to 15% of male infertility has an immunological origin, either due to repetitive infections or to autoimmune responses mainly affecting the epididymis, prostate, and testis. Clinical observations and epidemiological data clearly contradict the idea that the testis confers immune protection to the whole male genital tract. As a consequence, the epididymis, in which posttesticular spermatozoa mature and are stored, has raised some interest in recent years when it comes to its immune mechanisms. Indeed, sperm cells are produced at puberty, long after the establishment of self-tolerance, and they possess unique surface proteins that cannot be recognized as self. These are potential targets of the immune system, with the risk of inducing autoantibodies and consequently male infertility. Epididymal immunity is based on a finely tuned equilibrium between efficient immune responses to pathogens and strong tolerance to sperm cells. These processes rely on incompletely described molecules and cell types. This review compiles recent studies focusing on the immune cell types populating the epididymis, and proposes hypothetical models of the organization of epididymal immunity with a special emphasis on the immune response, while also discussing important aspects of the epididymal immune regulation such as tolerance and tumour control.

Nuclear Integrity but Not Topology of Mouse Sperm Chromosome is Affected by Oxidative DNA Damage.

Recent studies have revealed a well-defined higher order of chromosome architecture, named chromosome territories, in the human sperm nuclei. The purpose of this work was, first, to investigate the topology of a selected number of chromosomes in murine sperm; second, to evaluate whether sperm DNA damage has any consequence on chromosome architecture. Using fluorescence in situ hybridization, confocal microscopy, and 3D-reconstruction approaches we demonstrate that chromosome positioning in the mouse sperm nucleus is not random. Some chromosomes tend to occupy preferentially discrete positions, while others, such as chromosome 2 in the mouse sperm nucleus are less defined. Using a mouse transgenic model (Gpx5-/-) of sperm nuclear oxidation, we show that oxidative DNA damage does not disrupt chromosome organization. However, when looking at specific nuclear 3D-parameters, we observed that they were significantly affected in the transgenic sperm, compared to the wild-type. Mild reductive DNA challenge confirmed the fragility of the organization of the oxidized sperm nucleus, which may have unforeseen consequences during post-fertilization events. These data suggest that in addition to the sperm DNA fragmentation, which is already known to modify sperm nucleus organization, the more frequent and, to date, the less highly-regarded phenomenon of sperm DNA oxidation also affects sperm chromatin packaging.

Comprehensive overview of murine epididymal mononuclear phagocytes and lymphocytes: Unexpected populations arise.

Despite increasing evidence that epididymal immune disorders can lead to infertility, the cells and mechanisms underlying epididymal immunity remain poorly understood. In this study, we propose a rather exhaustive overview of innate and adaptive immune cells present in the murine caput and cauda epididymis. Using flow cytometry and a wide set of markers, we screened the broadest panel of immune cells ever, in this organ. For the first time, we unequivocally quantified the innate populations of monocytes, macrophages, and dendritic cells subtypes. We also revealed the presence of B cells, gamma delta T cells, and double negative T cells in the murine epididymis. They were localized by immunofluorescence stainings, and appeared to be all present in the interstitium and epithelium along the organ, but with respective preferential regional distribution. Altogether, these findings provide new insights on the actors and potential mechanisms involved in the immune responses against genital tract ascending pathogens and in the setting and maintenance of tolerance toward the sperm cells.

Liver X Receptors (LXRs) Alpha and Beta Play Distinct Roles in the Mouse Epididymis.

After its production in the testis, a spermatozoon has to undergo posttesticular maturation steps to become fully motile and fertile. The first step is epididymal maturation, during which immature spermatozoa are transformed into biochemically mature cells ready to proceed to the next step, capacitation, a physiological process occurring in the female genital tract. The biochemical transformations include modification of sperm lipid composition during epididymal transit, with significant changes in fatty acids, phospholipids, and sterols between the caput and the cauda epididymal spermatozoa. Although quantitative aspects of these changes are well documented for several mammalian species, molecular mechanisms governing these steps are poorly understood. Transgenic male mice invalidated for the two liver X receptors (LXRalpha and LXRbeta, nuclear oxysterol receptors regulating cholesterol and lipid metabolism) become sterile when aging, showing an epididymal phenotype. We used single-knockout-model mice to characterize the role of each LXR isoform during sperm maturation in the epididymis. We show here that although a certain redundancy exists in the functions of the two LXR isoforms, some physiological processes are more under the influence of only one of them. In both cases, aging males showed slight subfertility, associated with dyslipidemia, emphasizing the importance of lipid metabolism in relation with male fertility.

Oxidative DNA damage in mouse sperm chromosomes: Size matters.

Normal embryo and foetal development as well as the health of the progeny are mostly dependent on gamete nuclear integrity. In the present study, in order to characterize more precisely oxidative DNA damage in mouse sperm we used two mouse models that display high levels of sperm oxidative DNA damage, a common alteration encountered both in in vivo and in vitro reproduction. Immunoprecipitation of oxidized sperm DNA coupled to deep sequencing showed that mouse chromosomes may be largely affected by oxidative alterations. We show that the vulnerability of chromosomes to oxidative attack inversely correlated with their size and was not linked to their GC richness. It was neither correlated with the chromosome content in persisting nucleosomes nor associated with methylated sequences. A strong correlation was found between oxidized sequences and sequences rich in short interspersed repeat elements (SINEs). Chromosome position in the sperm nucleus as revealed by fluorescent in situ hybridization appears to be a confounder. These data map for the first time fragile mouse sperm chromosomal regions when facing oxidative damage that may challenge the repair mechanisms of the oocyte post-fertilization.

Natural Killer Cell Sensing of Infected Cells Compensates for MyD88 Deficiency but Not IFN-I Activity in Resistance to Mouse Cytomegalovirus.

In mice, plasmacytoid dendritic cells (pDC) and natural killer (NK) cells both contribute to resistance to systemic infections with herpes viruses including mouse Cytomegalovirus (MCMV). pDCs are the major source of type I IFN (IFN-I) during MCMV infection. This response requires pDC-intrinsic MyD88-dependent signaling by Toll-Like Receptors 7 and 9. Provided that they express appropriate recognition receptors such as Ly49H, NK cells can directly sense and kill MCMV-infected cells. The loss of any one of these responses increases susceptibility to infection. However, the relative importance of these antiviral immune responses and how they are related remain unclear. In humans, while IFN-I responses are essential, MyD88 is dispensable for antiviral immunity. Hence, a higher redundancy has been proposed in the mechanisms promoting protective immune responses against systemic infections by herpes viruses during natural infections in humans. It has been assumed, but not proven, that mice fail to mount protective MyD88-independent IFN-I responses. In humans, the mechanism that compensates MyD88 deficiency has not been elucidated. To address these issues, we compared resistance to MCMV infection and immune responses between mouse strains deficient for MyD88, the IFN-I receptor and/or Ly49H. We show that selective depletion of pDC or genetic deficiencies for MyD88 or TLR9 drastically decreased production of IFN-I, but not the protective antiviral responses. Moreover, MyD88, but not IFN-I receptor, deficiency could largely be compensated by Ly49H-mediated antiviral NK cell responses. Thus, contrary to the current dogma but consistent with the situation in humans, we conclude that, in mice, in our experimental settings, MyD88 is redundant for IFN-I responses and overall defense against a systemic herpes virus infection. Moreover, we identified direct NK cell sensing of infected cells as one mechanism able to compensate for MyD88 deficiency in mice. Similar mechanisms likely contribute to protect MyD88- or IRAK4-deficient patients from viral infections.

DNA oxidative damage in mammalian spermatozoa: where and why is the male nucleus affected?

Gamete DNA integrity is one key parameter conditioning reproductive success as well as the quality of life for the offspring. In particular, damage to the male nucleus can have profound negative effects on the outcome of fertilization. Because of the absence of repair activity of the quiescent mature spermatozoa it is easily subjected to nuclear damage, of which oxidative damage is by far the most prominent. In relation to the organization of the mammalian sperm nucleus we show here that one can correlate the nuclear regions of lower compaction with areas preferentially showing oxidative damage. More precisely, we show that oxidative DNA damage targets primarily histone-rich and nuclear matrix-attached domains located in the peripheral and basal regions of the mouse sperm nucleus. These particular sperm DNA domains were recently shown to be enriched in genes of paramount importance in postfertilization DNA replication events and in the onset of the embryonic developmental program. We propose that monitoring of sperm DNA oxidation using the type of assay presented here should be considered in clinical practice when one wants to estimate the integrity of the paternal nucleus along with more classical assays that essentially analyze DNA fragmentation and nucleus compaction.

Indoleamine 2,3-dioxygenase 1 (ido1) is involved in the control of mouse caput epididymis immune environment.

The epididymis maintains a state of immune tolerance towards spermatozoa while also protecting them and itself against infection and acute inflammation. The immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (Ido1) participates in this delicate local equilibrium. Using the mouse Ido1(-/-) model, we show here that the absence of IDO1 expression leads in the epididymis but not in serum to (1) an increase in the inflammatory state as evidenced by changes in the content of cytokines and chemokines, (2) the engagement of a Th1-driven inflammatory response as evidenced by changes in the Th17/Treg as well as Th1/Th2 equilibria, as well as (3) differences in the content of lipid intermediates classically involved in inflammation. Despite this more pronounced inflammatory state, Ido1(-/-) animals succeed in preserving the local epididymal immune situation due to the activation of compensatory mechanisms that are discussed.

MyD88 is crucial for the development of a protective CNS immune response to Toxoplasma gondii infection.

BACKGROUND: Toxoplasmosis is one of the most common parasitic infections in humans. It can establish chronic infection and is characterized by the formation of tissue cysts in the brain. The cysts remain largely quiescent for the life of the host, but can reactivate and cause life-threatening toxoplasmic encephalitis in immunocompromised patients, such as those with AIDS, neoplastic diseases and organ transplants. Toll-like receptor (TLR) adaptor MyD88 activation is required for the innate sensing of Toxoplasma gondii. Mice deficient in MyD88 have defective IL-12 and Th1 effector responses, and are highly susceptible to the acute phase of T. gondii infection. However, the role of this signaling pathway during cerebral infection is poorly understood and requires examination. METHOD: MyD88-deficient mice and control mice were orally infected with T. gondii cysts. Cellular and parasite infiltration in the peripheral organs and in the brain were determined by histology and immunohistochemistry. Cytokine levels were determined by ELISA and chemokine mRNA levels were quantified by real-time PCR (qPCR). RESULTS: Thirteen days after infection, a higher parasite burden was observed but there was no histological change in the liver, heart, lungs and small intestine of MyD88⁻/⁻ and MyD88⁺/⁺ mice. However, MyD88⁻/⁻ mice compared to MyD88⁺/⁺ mice were highly susceptible to cerebral infection, displayed high parasite migration to the brain, severe neuropathological signs of encephalitis and succumbed within 2 weeks of oral infection. Susceptibility was primarily associated with lower expression of Th1 cytokines, especially IL-12, IFN-γ and TNF-α, significant decrease in the expression of CCL3, CCL5, CCL7 and CCL19 chemokines, marked defect of CD8⁺ T cells, and infiltration of CD11b⁺ and F4/80⁺ cells in the brain. CONCLUSION: MyD88 is essential for the protection of mice during the cerebral installation of T. gondii infection. These results establish a role for MyD88 in T cell-mediated control of T. gondii in the central nervous system (CNS).

The immunobiology of the mammalian epididymis: the black box is now open!

Spermatozoa represent an immunologic challenge for the mammalian males. They are produced long after the establishment of the immune library of the individual and harbor specific spermatic antigens that are found nowhere else in other organs, tissues and cells. Consequently, spermatozoa are somehow "foreign" to the male adaptive immune system. In order not to elicit autoimmune responses that would be detrimental for male fertility, spermatozoa should be either physically separated from the adaptive immune response and/or, the immune system challenged by spermatic antigens must be efficiently silenced. Within the mammalian male genital tract it becomes more and more obvious that a range of strategies are at stake to ensure that the immune-stranger spermatozoa do not constitute an immunological issue. In this review the focus will be on the immune status of the epididymis tubule, in which spermatozoa that have left the testes will mature for approximately 2 weeks and may be stored for prolonged period of time. How the epididymal immune environment compares to that of the testis and what are the immune regulatory processes at work in the epididymal compartment will only be briefly described. Instead, this review will focus on recent data that highlight epididymal immune regulatory actors that partly explain/illustrate the rather complicated, fragile but nevertheless robust immune environment of the epididymis.

Les spermatozoïdes constituent un défi immunologique pour le mammifère mâle qui les fabrique. Elaborés longtemps après l'établissement de la librairie immunitaire de l'individu, ils portent des antigènes spécifiques de la lignée germinale qui leur confèrent un caractère "étranger" de nature à solliciter le système immunitaire. Afin de ne pas engager de réponses auto-immunes anti-spermatozoïde dont l'issue serait délétère pour la fertilité de l'individu, les spermatozoïdes doivent être gardés à l'abri des cellules immuno-compétentes, ou, si une réponse auto-immune anti-spermatozoïde est engagée, cette dernière doit être rendue silencieuse. Au sein du tractus génital mâle il apparaît de plus en plus clairement que différentes stratégies sont à l'œuvre afin d'empêcher que le spermatozoïde ne "challenge" le système immunitaire du mâle. Cette revue présente le statut immunologique de l'épididyme des mammifères dans lequel les spermatozoïdes qui ont quitté le testicule vont maturer pendant environ 2 semaines et être éventuellement stockés pour des périodes de temps variables. En quoi la situation immunologique de l'épididyme est-elle comparable ou différente de celle du testicule et quels sont les mécanismes immunitaires en action dans ce tubule seront présentés de façon non exhaustive. Une attention particulière sera donnée à des résultats récents qui mettent en avant quelques acteurs clefs de l'immuno-modulation et de la tolérance immune au sein de ce tissu épididymaire.

Functional activation of T cells by dendritic cells and macrophages exposed to the intracellular parasite Neospora caninum.

Neospora caninum is an intracellular protozoan pathogen that causes abortion in cattle. We studied how the interaction between murine conventional dendritic cells or macrophages and N. caninum influences the generation of cell-mediated immunity against the parasite. We first explored the invasion and survival ability of N. caninum in dendritic cells and macrophages. We observed that protozoa rapidly invaded and proliferated into these two cell populations. We then investigated how Neospora-exposed macrophages or dendritic cells distinguish between viable and non-viable (heat-killed tachyzoites and antigenic extract) parasites. Viable tachyzoites and antigenic extract, but not killed parasites, altered the phenotype of immature dendritic cells. Dendritic cells infected with viable parasites down-regulated the expression of MHC-II, CD40, CD80 and CD86 whereas dendritic cells exposed to N. caninum antigenic extract up-regulated the expression of MHC-II and CD40 and down-regulated CD80 and CD86 expression. Moreover, only viable tachyzoites and antigenic extract induced IL-12 synthesis by dendritic cells. MHC-II expression was up-regulated and CD86 expression was down-regulated at the surface of macrophages, regardless of the parasitic form was encountered. However, IL-12 secretion by macrophages was only observed under conditions using viable and heat-killed parasite. We then analysed how macrophages and dendritic cells were involved in inducing T-cell responses. T lymphocyte IFN-γ-secretion in correlation with IL-12 production occurred after interactions between T cells and dendritic cells exposed to viable tachyzoites or antigenic extract. By contrast, for macrophages IFN-γ production was IL-12-independent and only occurred after interactions between T cells and macrophages exposed to antigenic extract. Thus, N. caninum-induced activation of murine dendritic cells, but not that of macrophages, was associated with T cell IFN-γ production after IL-12 secretion.

Existence of CD8α-like dendritic cells with a conserved functional specialization and a common molecular signature in distant mammalian species.

The mouse lymphoid organ-resident CD8alpha(+) dendritic cell (DC) subset is specialized in Ag presentation to CD8(+) T cells. Recent evidence shows that mouse nonlymphoid tissue CD103(+) DCs and human blood DC Ag 3(+) DCs share similarities with CD8alpha(+) DCs. We address here whether the organization of DC subsets is conserved across mammals in terms of gene expression signatures, phenotypic characteristics, and functional specialization, independently of the tissue of origin. We study the DC subsets that migrate from the skin in the ovine species that, like all domestic animals, belongs to the Laurasiatheria, a distinct phylogenetic clade from the supraprimates (human/mouse). We demonstrate that the minor sheep CD26(+) skin lymph DC subset shares significant transcriptomic similarities with mouse CD8alpha(+) and human blood DC Ag 3(+) DCs. This allowed the identification of a common set of phenotypic characteristics for CD8alpha-like DCs in the three mammalian species (i.e., SIRP(lo), CADM1(hi), CLEC9A(hi), CD205(hi), XCR1(hi)). Compared to CD26(-) DCs, the sheep CD26(+) DCs show 1) potent stimulation of allogeneic naive CD8(+) T cells with high selective induction of the Ifngamma and Il22 genes; 2) dominant efficacy in activating specific CD8(+) T cells against exogenous soluble Ag; and 3) selective expression of functional pathways associated with high capacity for Ag cross-presentation. Our results unravel a unifying definition of the CD8alpha(+)-like DCs across mammalian species and identify molecular candidates that could be used for the design of vaccines applying to mammals in general.

Interleukin 17 receptor signaling is deleterious during Toxoplasma gondii infection in susceptible BL6 mice.

Th17 cells are involved in host defense against several pathogens. Using interleukin (IL) 17RA-deficient mice, we demonstrated reduced ileitis with diminished neutrophil recruitment and inflammatory lesions in the ileum, in the regional lymph node, in the spleen, and in the liver at day 7 and prolonged survival after Toxoplasma gondii infection. In addition, IL-17A antibody neutralization reduced inflammation and enhanced survival in BL6 mice. Diminished inflammation is associated with augmented interferon (IFN) gamma serum levels and enhanced production of IL-10 and IFN-gamma in cultured splenocytes upon antigen restimulation. Finally, cyst load and inflammation in the brain at 40 days are greater in surviving BL6 mice than in IL-17RA-deficient mice. In conclusion, oral T. gondii infection increases IL-17 expression and contributes to the inflammatory response, and IL-17 neutralization has a partial protective effect against fatal T. gondii-associated inflammation.