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PLoS Pathog. Mar 2012; 8(3): e1002560.
Published online Mar 1, 2012. doi:  10.1371/journal.ppat.1002560
PMCID: PMC3291656

Redundant Notch1 and Notch2 Signaling Is Necessary for IFNγ Secretion by T Helper 1 Cells During Infection with Leishmania major

David L. Sacks, Editor

Abstract

The protective immune response to intracellular parasites involves in most cases the differentiation of IFNγ-secreting CD4+ T helper (Th) 1 cells. Notch receptors regulate cell differentiation during development but their implication in the polarization of peripheral CD4+ T helper 1 cells is not well understood. Of the four Notch receptors, only Notch1 (N1) and Notch2 (N2) are expressed on activated CD4+ T cells. To investigate the role of Notch in Th1 cell differentiation following parasite infection, mice with T cell-specific gene ablation of N1, N2 or both (N1N2ΔCD4Cre) were infected with the protozoan parasite Leishmania major. N1N2ΔCD4Cre mice, on the C57BL/6 L. major-resistant genetic background, developed unhealing lesions and uncontrolled parasitemia. Susceptibility correlated with impaired secretion of IFNγ by draining lymph node CD4+ T cells and increased secretion of the IL-5 and IL-13 Th2 cytokines. Mice with single inactivation of N1 or N2 in their T cells were resistant to infection and developed a protective Th1 immune response, showing that CD4+ T cell expression of N1 or N2 is redundant in driving Th1 differentiation. Furthermore, we show that Notch signaling is required for the secretion of IFNγ by Th1 cells. This effect is independent of CSL/RBP-Jκ, the major effector of Notch receptors, since L. major-infected mice with a RBP-Jκ deletion in their T cells were able to develop IFNγ-secreting Th1 cells, kill parasites and heal their lesions. Collectively, we demonstrate here a crucial role for RBP-Jκ-independent Notch signaling in the differentiation of a functional Th1 immune response following L. major infection.

Author Summary

Infection with protozoan parasites of Leishmania species results in a spectrum of local or systemic diseases in humans and mammals. Overall, leishmaniasis afflicts around 12 million individuals in 88 countries worldwide. Cutaneous leishmaniasis is the most prevalent form of the disease. In order to better understand the complex molecular pathways leading to protection against the cutaneous form of the disease, we used the Leishmania major mouse model. Most mouse strains control L. major infection due to the development of a Th1 response, leading to secretion of IFNγ by T cells which promotes healing and resistance to reinfection. Notch signaling is a very conserved pathway in the regulation of cell differentiation and cell fate decision. However the contribution of Notch receptors in the response to parasite infection is not clear. In this study, we infected mice that do not express Notch1 and Notch2 receptors on the surface of their T cells. We show that these Notch receptors are key players in the development of a protective Th1 immune response against L. major. These results contribute to the understanding of the mechanisms involved in the development of a protective response against pathogens.


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