T Cells Get the Nod

Science Signaling  24 Nov 2009:
Vol. 2, Issue 98, pp. ec375
DOI: 10.1126/scisignal.298ec375

Nod2 is a member of the nucleotide-binding oligomerization domain receptor (NLR) family, which binds microbial products to play a key role in the cells mediating the innate immune response to pathogens. Shaw et al. report that Nod2 also functions in T cells, which are part of the adaptive immune response, to mount an effective response to the intracellular parasite Toxoplasma gondii. Survival of Nod2-deficient mice after T. gondii infection was impaired compared with that of wild-type mice. Unexpectedly, survival of infected mice deficient for the caspase-recruitment domain–containing kinase Ripk2, which is required for Nod2 signaling in innate immune cells, was not compromised. Examination of cells from peritoneal exudates showed that both Nod2-deficient and wild-type mice had similarly low parasite loads at early stages of infection but that after 12 days the Nod2-deficient mice had a much higher infection burden. The Nod2-deficient mice showed reduced concentration of circulating interferon-γ (IFN-γ) 7 days after infection. Natural killer cells and T helper 1 (TH1) are two main sources of IFN-γ, a cytokine essential for an effective immune response. The NK cell response to infection appeared the same as wild type in the Nod2-deficient animals; however, the Nod2-deficient mice had many fewer TH1 cells. Various experiments with wild-type and Nod2-deficient dendritic cells and transfer of wild-type and Nod2-deficient T cells into recipient mice demonstrated that the defect in TH1 cells appeared to be intrinsic to the T cells and not a consequence of impaired dendritic cell function. Survival of Nod2-deficient mice in response to T. gondii infection was improved if the animals received wild-type T cells. Compared with wild-type T cells, Nod2-deficient T cells failed to produce sufficient interleukin-2 (IL-2), which is a critical cytokine for T cell differentiation, to promote T helper cell differentiation. The gene encoding IL-2 is a target of the transcription factor NF-κB, and, when transfected into a fibroblast cell line, one subunit of NF-κB (c-Rel), NF-κB–inducing kinase (NIK), and Nod2 all coimmunoprecipitated together. Furthermore, when transfected into Jurkat T cells, maximal stimulation of an NF-κB reporter gene occurred when all three (c-Rel, NIK, and Nod2) were expressed together, suggesting that the three proteins synergize to drive gene expression. Consistent with a defect in NF-κB signaling, Nod2-deficient T cells exhibited decreased nuclear translocation of c-Rel after stimulation compared with wild-type cells. Thus, Nod2 appears to have a function in the adaptive immune system in T cell differentiation, and this role appears to be independent of its role as a pattern recognition receptor in the innate immune system (see Salek-Ardakani and Croft for commentary).

M. H. Shaw, T. Reimer, C. Sánchez-Valdepeñas, N. Warner, Y.-G. Kim. M. Fresno, G. Nuñez, T cell–intrinsic role of Nod2 in promoting type 1 immunity to Toxoplasma gondii. Nat. Immunol. 10, 1267–1274 (2009). [PubMed]

S. Salek-Ardakani, M. Croft, T cells need Nod too? Nat. Immunol. 10, 1231–1233 (2009). [PubMed]