Biomedical subjects

Catherine Ronet

Publications and source records attributed to Catherine Ronet.

9 recordsLinked to original sources

PubMed2006

TLR9 is required for the gut-associated lymphoid tissue response following oral infection of Toxoplasma gondii.

TLRs expressed by a variety of cells, including epithelial cells, B cells, and dendritic cells, are important initiators of the immune response following stimulation with various microbial products. Several of the TLRs require the adaptor protein, MyD88, which is an important mediator for the immune response following Toxoplasma gondii infection. Previously, TLR9-mediated innate immune responses were predominantly associated with ligation of unmethylated bacterial CpG DNA. In this study, we show that TLR9 is required for the Th1-type inflammatory response that ensues following oral infection with T. gondii. After oral infection with T. gondii, susceptible wild-type (WT; C57BL/6) but not TLR9(-/-) (B6 background) mice develop a Th1-dependent acute lethal ileitis; TLR9(-/-) mice have higher parasite burdens than control WT mice, consistent with depressed IFN-gamma-dependent parasite killing. A reduction in the total T cell and IFN-gamma-producing T cell frequencies was observed in the lamina propria of the TLR9(-/-) parasite-infected mice. TLR9 and type I IFN production was observed by cells from infected intestines in WT mice. TLR9 expression by dendritic cell populations is essential for their expansion in the mesenteric lymph nodes of infected mice. Infection of chimeric mice deleted of TLR9 in either the hemopoietic or nonhemopoietic compartments demonstrated that TLR9 expression by cells from both compartments is important for efficient T cell responses to oral infection. These observations demonstrate that TLR9 mediates the innate response to oral parasite infection and is involved in the development of an effective Th1-type immune response.

Administration, Oral↗

PubMed2005

NKT cells are critical for the initiation of an inflammatory bowel response against Toxoplasma gondii.

We demonstrated in this study the critical role of NKT cells in the lethal ileitis induced in C57BL/6 mice after infection with Toxoplasma gondii. This intestinal inflammation is caused by overproduction of IFN-gamma in the lamina propria. The implication of NKT cells was confirmed by the observation that NKT cell-deficient mice (Jalpha281(-/-)) are more resistant than C57BL/6 mice to the development of lethal ileitis. Jalpha281(-/-) mice failed to overexpress IFN-gamma in the intestine early after infection. This detrimental effect of NKT cells is blocked by treatment with alpha-galactosylceramide, which prevents death in C57BL/6, but not in Jalpha281(-/-), mice. This protective effect is characterized by a shift in cytokine production by NKT cells toward a Th2 profile and correlates with an increased number of mesenteric Foxp3 lymphocytes. Using chimeric mice in which only NKT cells are deficient in the IL-10 gene and mice treated with anti-CD25 mAb, we identified regulatory T cells as the source of the IL-10 required for manifestation of the protective effect of alpha-galactosylceramide treatment. Our results highlight the participation of NKT cells in the parasite clearance by shifting the cytokine profile toward a Th1 pattern and simultaneously to immunopathological manifestation when this Th1 immune response remains uncontrolled.

Acute Disease↗

PubMed2004

Expansion and function of CD8+ T cells expressing Ly49 inhibitory receptors specific for MHC class I molecules.

MHC class I-specific Ly49 inhibitory receptors regulate NK cell activation, thereby preventing autologous damage to normal cells. Ly49 receptors are also expressed on a subset of CD8+ T cells whose origin and function remain unknown. We report here that, despite their phenotypic and cytolytic similarities, Ly49+CD8+ T cells and conventional Ly49-CD44high memory-phenotype CD8+ T cells present strikingly distinct features. First, under steady state conditions Ly49+CD8+ T cells are poor cytokine producers (TNF-alpha and IFN-gamma) upon TCR triggering. Second, Ly49+CD8+ T cells are not induced upon various settings of Ag immunization or microbial challenge. However, Ly49 can be induced on a fraction of self-specific CD8+ T cells if CD4+ T cells are present. Finally, the size of the Ly49+CD8+ T cell subset is selectively reduced in the absence of STAT1. These results indicate that Ly49 expression is associated with a differentiation program of cytolytic CD8+ T cells triggered upon chronic antigenic exposure. They further suggest that the size of the Ly49+CD8+ T cell subset marks a history of CD8+ T cell activation that might preferentially result from endogenous inducers of inflammation rather than from microbial infections.

Animals↗

PubMed2004

Toxoplasma gondii and mucosal immunity.

Toxoplasma gondii, an intracellular parasite infects the host through the oral route. Infection induces a cascade of immunological events that involve both the components of the innate and adaptative immune responses. Alteration of the homeostatic balance of infected intestine results in an acute inflammatory ileitis in certain strains of inbred mice. Both the infected enterocytes as well as the CD4 T cells from the lamina propria produce chemokines and cytokines that are necessary to clear the parasite whereas CD8 intraepithelial lymphocytes secrete transforming growth factor beta that reduces the inflammation. In this review, we describe the salient features of this complex network of interactions among the different components of the gut-associated lymphoid tissue cell population that are induced after oral infection with T. gondii.

Animals↗

PubMed2003

The intratumoral application of poly-G-oligodeoxynucleotides does not augment the naturally induced antitumoral CD8-T-cell response in P815 mastocytomas.

DNA sequences containing CpG have been described to induce a strong immune reaction by acting on a variety of immune cells including a strong and pronounced antitumoral response. Poly-G-oligodeoxynucleotides (ODNs) on the other hand have been attributed the preferential induction of CD8-T-cell proliferation when used in vitro. This activity led us to the investigation of the possible antitumoral properties of poly-G-ODNs in an established CD8-dependent tumor eradication model. We used the well described poly-G-ODN 1628 in its capacity to enhance antitumoral CD8 response in the cutaneous mastocytoma P815. When injecting 30 microg of the purified phosphothioate-modified oligo into the tumor bearing area of P815 challenged mice for up to 12 consecutive days we did not observe increased tumor rejection as compared to the group of mice injected with a control oligo. The 1628-injected mice did not produce higher numbers of P815-specific CD8 cells as measured by P1A-, and P1E-tetramer staining and Immunoscope analysis. Furthermore, tumor-specific CD8 cells in 1628 did not show enhanced antitumoral cytotoxicity when analyzing lymphocyte-tumor cell co-cultures or transcription of the cytotoxic CD8-cell associated molecules interferon gamma, FAS ligand, perforin, or granzyme B by quantitative real-time RT-PCR. These experiments show that there is no enhanced induction of an antitumoral CD8 response after in situ administration of poly-G-ODNs in the P815 mastocytoma model.

Animals↗

PubMed2003

Total enantioselective synthesis and in vivo biological evaluation of a novel fluorescent BODIPY alpha-galactosylceramide.

Natural killer T (NKT) cells are a distinct subset of mature lymphocytes endowed with features of activated and regulatory T cells. alpha-Galactosylceramides (alpha-GalCers), the synthetic prototype of which is KRN7000, are the only natural reagents recognised by the T-cell receptor of NKT cells. The alpha-GalCer-activated NKT cells promptly release IFN gamma and IL-4 (IFN=interferon; IL=interleukin) and undergo apoptotic death within hours. In mice, activated NKT cells are responsible for antitumour activity and protection against autoimmune diseases. KRN7000 can thus be considered as the root of a family of novel immunoregulatory drugs. To get insights into the in vivo behaviour of alpha-galactosylceramides, an original fluorescent derivative has been prepared by following a convergent synthetic scheme. This strategy allows the introduction of different acyl chains, carbohydrate residues and various labels in the final steps of the synthesis. The fluorescent BODIPY probe derived from a versatile glycolipid precursor is as active as KRN7000 for inducing apoptosis of liver NKT cells. Fluorescence was detected in peritoneal macrophages and splenic antigen-presenting cells, in Kupffer-like cells in the liver, but not in lymphocytes.

Animals↗

PubMed2002

Phenotypic and functional differences between NKT cells colonizing splanchnic and peripheral lymph nodes.

NKT cells are considered unconventional T cells. First, they are restricted by a nonclassical MHC class I molecule, CD1d, which presents glycolipids; second, their TCR repertoire is very limited. After stimulation by their TCR, NKT cells rapidly release large amounts of cytokines, such as IL-4 and IFN-gamma. Little is known about NKT cells present in lymph nodes. In the present report we show that NKT cells are differently distributed in various lymph nodes and are, for instance, abundant in pancreatic and mesenteric lymph nodes of C57BL/6 mice and nonobese diabetic mice. The high frequency of NKT cells in splanchnic lymph nodes is not simply a consequence of inflammatory signals, as draining lymph nodes still contain low frequencies of NKT cells after IFA or CFA injections. NKT cells from splanchnic lymph nodes harbor a Vbeta repertoire similar to that of splenic and liver NKT cells, in contrast to peripheral NKT cells that are not biased toward Vbeta8 segments. Analysis of cytokine production by NKT cells from splanchnic lymph nodes reveals that they produce at least as much IL-4 as IFN-gamma, in contrast to NKT cells from other organs (spleen, liver, and peripheral lymph nodes), which produce much more IFN-gamma than IL-4. These specific features of NKT cells from splanchnic lymph nodes might explain their protective action against the development of pathogenic Th1 cells in type 1 diabetes.

Animals↗

PubMed2002

NKT cells-containing inflammatory lesions induced by Yersinia pseudotuberculosis glycolipids.

Valpha14-expressing NKT (invNKT) cells are a population of non-conventional T lymphocytes (TL) that bridge mammalian innate and adaptive immunity. Their role in infectious diseases and inflammatory processes is still largely ununderstood. A previous report has shown that an acute granulomatous-like reaction can be elicited by sub-cutaneous injection of Mycobacterium tuberculosis glycolipids in mice, and that recruitment of invNKT cells at the injection site is instrumental in this process. Here, we describe the mouse response to enterobacterium Yersinia pseudotuberculosis glycolipids extracts during the first week post injection. The cellular reaction is an acute inflammatory infiltrate where TL are abundant from early times on. InvNKT cells are present in the lesions, detectable as early as day 1 post injection. They compose all of the Valpha14-expressing TL, although conventional T cells expressing non-Valpha14 alpha-chains can be detected. The reaction is strictly dependent on ester-linked fatty acids as mild alkaline treatment of the extract prior to injection results in the absence of analysable lesions. Thus, glycolipids from Yersinia induce inflammatory lesions comparable to those induced by mycobacteria glycolipids, in spite of the totally different cell wall composition in the two genera. Moreover, the present findings show that invNKT cell response is not unique to mycobacterial glycolipids.

Animals↗

PubMed2002

Natural killer T cells restricted by the monomorphic MHC class 1b CD1d1 molecules behave like inflammatory cells.

Murine Valpha14(inv)T cells (NKT cells), restricted by the CD1d1 MHC 1b molecules, are a distinctive subset of T cells endowed with pleiotropic functions. CD1d1-restricted NKT cells infiltrate the granulomas induced by the s.c. injection of mycobacterial phosphatidylinositoldimannoside (PIM(2)) but not of its deacylated derivative. NKT cells are detectable as early as 6 hours following the injection. Although the molecular structure of PIM(2) meets the requirements for presentation by CD1d1, Ab blocking and adoptive transfer experiments of wild-type NKT cells into CD1d1(-/-) mice show that CD1d1 expression is not required for the early recruitment of NKT cells to the injection site. This conclusion was confirmed by the finding that IL-12Rbeta(-/-) and CD40(-/-) mice were able to recruit NKT cells after PIM(2) challenge. Moreover, the injection of alpha-galactosylceramide, an NKT cell ligand that is recognized in the context of CD1d1, promoted only a minor recruitment of NKT cells. By contrast, injection of beta-galactosylceramide, a synthetic glycolipid that binds to CD1d1 but does not activate the CD1d/TCR pathway, resulted in the development of large granulomas rich in NKT cells. Finally, local injection of TNF-alpha mimics the effect of glycolipids. It is concluded that NKT cells migrate to and accumulate at inflammatory sites in the same way as other cells of the innate immune system and that migration to and accumulation at inflammatory sites are processes independent of the CD1d1 molecule.

Adoptive Transfer↗