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

PLoS Pathogens

Fabienne Tacchini-Cottier¹  Floriane Auderset¹  Florian Desgranges¹  Steffen Schuster¹  Manuel Coutaz¹  Ute Koch²  Freddy Radtke²  Estelle Merck³  H. Robson MacDonald³ 

[1] Department of Biochemistry, WHO Immunology Research and Training Center, University of Lausanne, Epalinges, Switzerland;Ecole Polytechnique Fédérale de Lausanne, Swiss Experimental Cancer Research, Lausanne, Switzerland;Ludwig Institute for Cancer Research Ltd, Lausanne Branch, University of Lausanne, Epalinges, Switzerland

关键词: T helper cells;    Cell differentiation;    Parasitic diseases;    Secretion;    T cells;    Notch signaling;    T cell receptors;    Cytokines;   

DOI  :  10.1371/journal.ppat.1002560

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY