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

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

Caractérisation moléculaire et fonctionnelle de hOSCAR, nouveau récepteur associé à la chaîne FcRg (rôle dans la présentation antigénique et l'activation des cellules myéloïdes)

Le système immunitaire est régulé par des récepteurs activateurs et inhibiteurs, dont ceux signalant respectivement par des motifs à tyrosine, les ITAM et ITIM. hOSCAR est un nouveau récepteur exprimé uniquement par les cellules myéloïdes et associé à la chaîne à ITAM, FcRg. Dans les cellules dendritiques (DC), l'engagement d'hOSCAR permet l'endocytose et la présentation antigénique en CMH de classe II. De plus, hOSCAR est capable de déclencher un programme de maturation des DC (marqueurs d'activation, production de cytokines/chimiokines). L'engagement d'hOSCAR en combinaison avec des ligands de TLR augmente la capacité des DC à stimuler les cellules T naïves, module le profil des cytokines produites par les DC et peut influencer l'orientation Th1. hOSCAR est également capable d'activer la réponse pro-inflammatoire des monocytes et neutrophiles. hOSCAR est donc un nouveau récepteur activateur impliqué dans l'initiation et la modulation des réponses des immunités innée et adaptativeLYON1-BU.Sciences (692662101) / SudocSudocFranceF

N1 and N2 alone can drive CD4⁺ Th1 differentiation.

<p>(A) N1^ΔCD4Cre, N2^ΔCD4Cre, N1N2^ΔCD4Cre, and control mice were infected with 3×10⁶<i>L. major</i> promastigotes and lesion size measured weekly. Data are represented as the mean of lesion size ± SEM with n≥3 mice per group. (B) Parasite load in the lesion was assessed by LDA 6 weeks after infection. Mean parasite number is given ± SEM (n≥3 mice per group) (C, D) Six weeks after infection, IFNγ (C), IL-4 and IL-13 (D) secretion was assessed in supernatant of dLN cells restimulated or not with UV-irradiated <i>L. major</i> for 72 h. Histograms show the mean cytokine secretion ± SEM (n≥3 mice per group). n.d. not-detectable, n.s. not significant. * p-value<0.05 versus control mice.</p

The impact of Notch signaling on Th1 differentiation is RBP-Jκ-independent.

<p>(A) RBP-Jκ^ΔCD4Cre and RBP-Jκ<i>^lox/lox</i> mice were infected s.c. with 3×10⁶<i>L. major</i> and lesion size measured weekly. Group mean of lesion size ± SEM for n≥3 mice per group is shown. (B) Parasite load in footpad was analyzed by LDA 5 weeks post infection. Data represent mean parasite number ± SEM for n≥3 mice per group. (C, D) IFNγ (C), IL-4, IL-13 and IL-5 (D) levels were measured in supernatant of dLN cells isolated from <i>L. major</i>-infected mice 5 weeks post infection and restimulated for 72 h with or without UV-treated <i>L. major</i>. Group mean of cytokine secretion ± SEM is given (n≥3 mice per group). n.s. not significant. * p-value<0.05 versus control mice.</p