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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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Role for Nod2 in T cell-induced colitis. (a) Body weights of Rag1−/− recipients of purified CD4+CD25−CD45RBhi T cells from Nod2−/− or wild-type mice, represented as percent of initial (day 0) weight. (b) Gross morphology of the colon from the recipient mice in (a) at eight weeks post reconstitution. (c) Left, histology of small intestine and colonic tissues from the mice in (a). Right, severity of intestinal inflammation in the mice in (a) was assessed by histologic scoring on three major categories (extent of epithelial damage, level of involvement, and inflammatory cell infiltration). (d) Mesenteric lymph nodes were harvested from the mice in (a) and restimulated with α-CD3 for 24 h. IFN-γ concentrations in the culture supernatants were determined by ELISA. Data shown are representative of two experiments with n=5 mice per group. * P< 0.05; ** P < 0.005; *** P < 0.0005; † P < 0.0001.
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Figure 7: Role for Nod2 in T cell-induced colitis. (a) Body weights of Rag1−/− recipients of purified CD4+CD25−CD45RBhi T cells from Nod2−/− or wild-type mice, represented as percent of initial (day 0) weight. (b) Gross morphology of the colon from the recipient mice in (a) at eight weeks post reconstitution. (c) Left, histology of small intestine and colonic tissues from the mice in (a). Right, severity of intestinal inflammation in the mice in (a) was assessed by histologic scoring on three major categories (extent of epithelial damage, level of involvement, and inflammatory cell infiltration). (d) Mesenteric lymph nodes were harvested from the mice in (a) and restimulated with α-CD3 for 24 h. IFN-γ concentrations in the culture supernatants were determined by ELISA. Data shown are representative of two experiments with n=5 mice per group. * P< 0.05; ** P < 0.005; *** P < 0.0005; † P < 0.0001.

Mentions: As an additional test to evaluate the role of Nod2 in regulating T cell function, we utilized a mouse model of colitis whereby the transfer of purified CD4+CD25−CD45RBhi T cells into Rag1−/− mice leads to colitis driven by TH1 cytokines13, 14. Wild-type CD4+CD25−CD45RBhi T cells predictably induced wasting disease (Figure 7a). In contrast, Rag1−/− mice reconstituted with Nod2−/− CD4+CD25−CD45RBhi T cells remained healthy and none exhibited wasting disease, as evidenced by the increase in body weight (Figure 7a). At gross examination, the large intestine was thickened in Rag1−/− recipients of wild-type, but not Nod2−/− CD4+CD25−CD45RBhi cells (Figure 7b). Microscopic examination of the small and large intestine isolated from Rag1−/− mice reconstituted with wild-type CD4+CD25−CD45RBhi cells revealed an increase in inflammatory cell accumulation (Figure 7c). In contrast, sections from the intestines of Rag1−/− recipients of Nod2−/− CD4+CD25−CD45RBhi cells revealed substantially less severe histological lesions (Figure 7c). Consistent with the microscopic examination, Rag1−/− recipients of Nod2-deficient T cells had lower histologic scores (Figure 7c), and T cells in the mesenteric lymph nodes of these mice produced less IFN-γ (Figure 7d). Taken together, these data support a direct role of Nod2 in regulating T cell function.


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)

Role for Nod2 in T cell-induced colitis. (a) Body weights of Rag1−/− recipients of purified CD4+CD25−CD45RBhi T cells from Nod2−/− or wild-type mice, represented as percent of initial (day 0) weight. (b) Gross morphology of the colon from the recipient mice in (a) at eight weeks post reconstitution. (c) Left, histology of small intestine and colonic tissues from the mice in (a). Right, severity of intestinal inflammation in the mice in (a) was assessed by histologic scoring on three major categories (extent of epithelial damage, level of involvement, and inflammatory cell infiltration). (d) Mesenteric lymph nodes were harvested from the mice in (a) and restimulated with α-CD3 for 24 h. IFN-γ concentrations in the culture supernatants were determined by ELISA. Data shown are representative of two experiments with n=5 mice per group. * P< 0.05; ** P < 0.005; *** P < 0.0005; † P < 0.0001.
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Figure 7: Role for Nod2 in T cell-induced colitis. (a) Body weights of Rag1−/− recipients of purified CD4+CD25−CD45RBhi T cells from Nod2−/− or wild-type mice, represented as percent of initial (day 0) weight. (b) Gross morphology of the colon from the recipient mice in (a) at eight weeks post reconstitution. (c) Left, histology of small intestine and colonic tissues from the mice in (a). Right, severity of intestinal inflammation in the mice in (a) was assessed by histologic scoring on three major categories (extent of epithelial damage, level of involvement, and inflammatory cell infiltration). (d) Mesenteric lymph nodes were harvested from the mice in (a) and restimulated with α-CD3 for 24 h. IFN-γ concentrations in the culture supernatants were determined by ELISA. Data shown are representative of two experiments with n=5 mice per group. * P< 0.05; ** P < 0.005; *** P < 0.0005; † P < 0.0001.
Mentions: As an additional test to evaluate the role of Nod2 in regulating T cell function, we utilized a mouse model of colitis whereby the transfer of purified CD4+CD25−CD45RBhi T cells into Rag1−/− mice leads to colitis driven by TH1 cytokines13, 14. Wild-type CD4+CD25−CD45RBhi T cells predictably induced wasting disease (Figure 7a). In contrast, Rag1−/− mice reconstituted with Nod2−/− CD4+CD25−CD45RBhi T cells remained healthy and none exhibited wasting disease, as evidenced by the increase in body weight (Figure 7a). At gross examination, the large intestine was thickened in Rag1−/− recipients of wild-type, but not Nod2−/− CD4+CD25−CD45RBhi cells (Figure 7b). Microscopic examination of the small and large intestine isolated from Rag1−/− mice reconstituted with wild-type CD4+CD25−CD45RBhi cells revealed an increase in inflammatory cell accumulation (Figure 7c). In contrast, sections from the intestines of Rag1−/− recipients of Nod2−/− CD4+CD25−CD45RBhi cells revealed substantially less severe histological lesions (Figure 7c). Consistent with the microscopic examination, Rag1−/− recipients of Nod2-deficient T cells had lower histologic scores (Figure 7c), and T cells in the mesenteric lymph nodes of these mice produced less IFN-γ (Figure 7d). Taken together, these data support a direct role of Nod2 in regulating T cell function.

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