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

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.

Involvement of Notch in Activation and Effector Functions of γδ T cells

“…Activation of the Notch signaling pathway leads to the induction of c-Myc expression in immune cells (36), which was also observed in gd T cells. Recent reports suggest that Notch signaling involves both canonical and noncanonical pathways in T cells, and these interactions will influence cell fate decisions and functions (32,37). We therefore analyzed the expression of mRNA for Hes1 and NF-kB in BrHPP-stimulated gd T cells after inhibiting the Notch signaling by GSI-X.…”

Regulation of innate and adaptive immunity by Notch

“…In contrast to the results obtained following γ-secretase treatment, functional T H 1 cells could develop in response to infection in mice that do not activate RBPJ because of dominant-negative MAML expression 77 . In the same line, mice deficient for RBPJ expression in their T cells were also able to mount a protective T H 1 cell response following infection with the parasite Leishmania major 78 . Altogether, these studies suggest that T H 1 cell differentiation does not involve canonical Notch signalling, defined as the association of the Notch intracellular domain (NICD) with RBPJ in the nucleus.…”

Notch Signaling Regulates the Homeostasis of Tissue-Restricted Innate-like T Cells

“…Similarly, conventional CD4 and CD8 T cells are unable to produce IFN-g during a graft-versus-host reaction (47) or parasite infection (33) in the absence of Notch signaling. Notch is known to regulate IFN-g transcription by binding to the IFN-g CNS22 enhancer and acts in synergy with T-bet to control the production of IFN-g in T cells (48,49).…”