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T cell-intrinsic role of Nod2 in promoting type 1 immunity to Toxoplasma gondii.

Shaw MH, Reimer T, Sánchez-Valdepeñas C, Warner N, Kim YG, Fresno M, Nuñez G - Nat. Immunol. (2009)

Bottom Line: Nod2 deficiency results in an impaired immune response to bacterial pathogens.Nod2(-/-) CD4(+) T cells had poor helper T cell differentiation, which was associated with impaired production of interleukin 2 (IL-2) and nuclear accumulation of the transcription factor subunit c-Rel.Our data demonstrate a T cell-intrinsic role for Nod2 signaling that is critical for host defense against T. gondii.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA.

ABSTRACT
Nod2 belongs to the nucleotide-binding oligomerization domain receptor (NLR) family of proteins, which function as intracellular pathogen sensors in innate immune cells. Nod2 deficiency results in an impaired immune response to bacterial pathogens. However, how this protein promotes host defense against intracellular parasites is unknown. Here we found that Nod2(-/-) mice had less clearance of Toxoplasma gondii and lower interferon-gamma (IFN-gamma) production. Reconstitution of T cell-deficient mice with Nod2(-/-) T cells followed by T. gondii infection demonstrated a T cell-intrinsic defect. Nod2(-/-) CD4(+) T cells had poor helper T cell differentiation, which was associated with impaired production of interleukin 2 (IL-2) and nuclear accumulation of the transcription factor subunit c-Rel. Our data demonstrate a T cell-intrinsic role for Nod2 signaling that is critical for host defense against T. gondii.

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Nod2 in host defense against T. gondii infection. Wild-type (WT), Nod2−/−, RICK−/− and Ifng−/− mice were challenged i.p. with 20 cysts of the ME49 strain of T. gondii. (a) Survival was monitored over 30 days. (b) The percentage of tachyzoite-infected peritoneal exudate cells (PEC) was enumerated on day 7. (c) Cytospins of PECs from day 12 infected wild-type and Nod2−/− mice were prepared and stained to visualize intracellular parasites (left panels 20× magnification; right panles 100× magnification; arrows indicate parasites). (d) On day 12 post-challenge, the percentage of infected PECs in infected wild-type and Nod2−/− mice was determined. In (a) the P value was determined using the Mantel-Cox log-rank test and is representative of at least four similar experiments with 5–20 mice per group. In (b-d) values shown are the mean ± s.d. of infected PECs and are representative of at least three experiments with 3–5 mice per group.
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Figure 1: Nod2 in host defense against T. gondii infection. Wild-type (WT), Nod2−/−, RICK−/− and Ifng−/− mice were challenged i.p. with 20 cysts of the ME49 strain of T. gondii. (a) Survival was monitored over 30 days. (b) The percentage of tachyzoite-infected peritoneal exudate cells (PEC) was enumerated on day 7. (c) Cytospins of PECs from day 12 infected wild-type and Nod2−/− mice were prepared and stained to visualize intracellular parasites (left panels 20× magnification; right panles 100× magnification; arrows indicate parasites). (d) On day 12 post-challenge, the percentage of infected PECs in infected wild-type and Nod2−/− mice was determined. In (a) the P value was determined using the Mantel-Cox log-rank test and is representative of at least four similar experiments with 5–20 mice per group. In (b-d) values shown are the mean ± s.d. of infected PECs and are representative of at least three experiments with 3–5 mice per group.

Mentions: To assess whether NLRs participate in host defense against T. gondii, mice genetically deficient in various NLR family members were inoculated intraperitoneally (i.p.) with the avirulent ME49 strain of T. gondii, and the survival of the animals was monitored. Among the mutant mice strains tested, mice lacking Nod1, Nlrc4, ASC, Nlrp6 and Nlrp12 exhibited normal resistance to T. gondii infection; only Nod2-deficient mice exhibited impaired survival after T. gondii infection (Figure 1a; Supplementary Figure 1). The enhanced susceptibility of Nod2- animals was clearly distinct from that of mice lacking IL-12p35 or IFN-γ (Figure 1a). Unexpectedly, mice lacking RICK (also called Rip2), a caspase-recruitment domain (CARD)-containing kinase that has been implicated in Nod1 and Nod2 signaling8, were resistant to parasite infection (Figure 1a). The resistance of the Nod2-deficient animals to acute infection was confirmed by examining the peritoneal exudate cells (PECs) harvested from the peritoneum cavity on day 7 post-infection. In both Nod2−/− and wild-type animals, less than 1% of the cells were infected with the parasite; in contrast greater than 20% of the PECs recovered at the same time point from Ifng−/− mice were infected (Figure 1b). However, examination of PECs harvested from infected Nod2-deficient mice on day 12 revealed high numbers of infiltrating mononuclear cells harboring parasites as well as numerous extracellular parasites (Figure 1c). Furthermore, in contrast to wild-type mice, which contained few (<1%) infected cells and lower concentrations of serum IFN-γ, there was a 20-fold increase in the number of cells infected with tachyzoites and high concentrations of circulating IFN-γ in Nod2−/− mice (Figure 1d and data not shown). Together, these results suggest that the susceptibility of Nod2−/− animals following parasite challenge appears to be due to a delayed impairment in the ability to control parasite replication at the site of infection.


T cell-intrinsic role of Nod2 in promoting type 1 immunity to Toxoplasma gondii.

Shaw MH, Reimer T, Sánchez-Valdepeñas C, Warner N, Kim YG, Fresno M, Nuñez G - Nat. Immunol. (2009)

Nod2 in host defense against T. gondii infection. Wild-type (WT), Nod2−/−, RICK−/− and Ifng−/− mice were challenged i.p. with 20 cysts of the ME49 strain of T. gondii. (a) Survival was monitored over 30 days. (b) The percentage of tachyzoite-infected peritoneal exudate cells (PEC) was enumerated on day 7. (c) Cytospins of PECs from day 12 infected wild-type and Nod2−/− mice were prepared and stained to visualize intracellular parasites (left panels 20× magnification; right panles 100× magnification; arrows indicate parasites). (d) On day 12 post-challenge, the percentage of infected PECs in infected wild-type and Nod2−/− mice was determined. In (a) the P value was determined using the Mantel-Cox log-rank test and is representative of at least four similar experiments with 5–20 mice per group. In (b-d) values shown are the mean ± s.d. of infected PECs and are representative of at least three experiments with 3–5 mice per group.
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Figure 1: Nod2 in host defense against T. gondii infection. Wild-type (WT), Nod2−/−, RICK−/− and Ifng−/− mice were challenged i.p. with 20 cysts of the ME49 strain of T. gondii. (a) Survival was monitored over 30 days. (b) The percentage of tachyzoite-infected peritoneal exudate cells (PEC) was enumerated on day 7. (c) Cytospins of PECs from day 12 infected wild-type and Nod2−/− mice were prepared and stained to visualize intracellular parasites (left panels 20× magnification; right panles 100× magnification; arrows indicate parasites). (d) On day 12 post-challenge, the percentage of infected PECs in infected wild-type and Nod2−/− mice was determined. In (a) the P value was determined using the Mantel-Cox log-rank test and is representative of at least four similar experiments with 5–20 mice per group. In (b-d) values shown are the mean ± s.d. of infected PECs and are representative of at least three experiments with 3–5 mice per group.
Mentions: To assess whether NLRs participate in host defense against T. gondii, mice genetically deficient in various NLR family members were inoculated intraperitoneally (i.p.) with the avirulent ME49 strain of T. gondii, and the survival of the animals was monitored. Among the mutant mice strains tested, mice lacking Nod1, Nlrc4, ASC, Nlrp6 and Nlrp12 exhibited normal resistance to T. gondii infection; only Nod2-deficient mice exhibited impaired survival after T. gondii infection (Figure 1a; Supplementary Figure 1). The enhanced susceptibility of Nod2- animals was clearly distinct from that of mice lacking IL-12p35 or IFN-γ (Figure 1a). Unexpectedly, mice lacking RICK (also called Rip2), a caspase-recruitment domain (CARD)-containing kinase that has been implicated in Nod1 and Nod2 signaling8, were resistant to parasite infection (Figure 1a). The resistance of the Nod2-deficient animals to acute infection was confirmed by examining the peritoneal exudate cells (PECs) harvested from the peritoneum cavity on day 7 post-infection. In both Nod2−/− and wild-type animals, less than 1% of the cells were infected with the parasite; in contrast greater than 20% of the PECs recovered at the same time point from Ifng−/− mice were infected (Figure 1b). However, examination of PECs harvested from infected Nod2-deficient mice on day 12 revealed high numbers of infiltrating mononuclear cells harboring parasites as well as numerous extracellular parasites (Figure 1c). Furthermore, in contrast to wild-type mice, which contained few (<1%) infected cells and lower concentrations of serum IFN-γ, there was a 20-fold increase in the number of cells infected with tachyzoites and high concentrations of circulating IFN-γ in Nod2−/− mice (Figure 1d and data not shown). Together, these results suggest that the susceptibility of Nod2−/− animals following parasite challenge appears to be due to a delayed impairment in the ability to control parasite replication at the site of infection.

Bottom Line: Nod2 deficiency results in an impaired immune response to bacterial pathogens.Nod2(-/-) CD4(+) T cells had poor helper T cell differentiation, which was associated with impaired production of interleukin 2 (IL-2) and nuclear accumulation of the transcription factor subunit c-Rel.Our data demonstrate a T cell-intrinsic role for Nod2 signaling that is critical for host defense against T. gondii.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA.

ABSTRACT
Nod2 belongs to the nucleotide-binding oligomerization domain receptor (NLR) family of proteins, which function as intracellular pathogen sensors in innate immune cells. Nod2 deficiency results in an impaired immune response to bacterial pathogens. However, how this protein promotes host defense against intracellular parasites is unknown. Here we found that Nod2(-/-) mice had less clearance of Toxoplasma gondii and lower interferon-gamma (IFN-gamma) production. Reconstitution of T cell-deficient mice with Nod2(-/-) T cells followed by T. gondii infection demonstrated a T cell-intrinsic defect. Nod2(-/-) CD4(+) T cells had poor helper T cell differentiation, which was associated with impaired production of interleukin 2 (IL-2) and nuclear accumulation of the transcription factor subunit c-Rel. Our data demonstrate a T cell-intrinsic role for Nod2 signaling that is critical for host defense against T. gondii.

Show MeSH
Related in: MedlinePlus