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.
Highlights
Following activation by pathogens, naıve CD4+ T cells can differentiate into several functionally distinct T helper (Th) subsets, defined by the cytokines they secrete
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
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
Summary
Naıve CD4+ T cells can differentiate into several functionally distinct T helper (Th) subsets, defined by the cytokines they secrete. CD4+ Th1 cells secrete IFNc as a signature cytokine and the transcription factor T-bet is essential for their differentiation. Cytokines such as IL-12 contribute to Th1 cell differentiation, Th1 cells can be generated in the absence of cytokine signaling, demonstrating a role for other molecules in this process. Among these are Notch receptors and their ligands (Reviewed in [1,2]). In the T cell lineage, the Notch receptor is essential for the development of ab T cells [4], and Notch plays a poorly understood role in the differentiation of peripheral Th cell subsets (reviewed in [1,5])
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