Notch signaling regulates PD-1 expression during CD8(+) T-cell activation.

Programmed cell death 1 (PD-1) is an inhibitory receptor involved in T-cell activation, tolerance and exhaustion. Little is known on how the expression of PD-1 is controlled during T-cell activation. Recent studies demonstrated that NFATc1 and IRF9 regulate Pdcd1 (PD-1) transcription and that T-bet acts as a transcriptional repressor. In this study, we have investigated the role of the Notch signaling pathway in PD-1 regulation. Using specific inhibitors of the Notch signaling pathway, we showed decreased PD-1 expression and inhibition of Pdcd1 transcription by activated CD8(+) T cells. Chromatin immunoprecipitation further showed occupancy of the Pdcd1 promoter with RBPJk and Notch1 intracellular domain at RBPJk-binding sites. Our results identify the Notch signaling pathway as an important regulator of PD-1 expression by activated CD8(+) T cells.

CD40-activated B cells can efficiently prime antigen-specific naïve CD8+ T cells to generate effector but not memory T cells.

BACKGROUND: The identification of the signals that should be provided by antigen-presenting cells (APCs) to induce a CD8(+) T cell response in vivo is essential to improve vaccination strategies using antigen-loaded APCs. Although dendritic cells have been extensively studied, the ability of other APC types, such as B cells, to induce a CD8(+) T cell response have not been thoroughly evaluated. METHODOLOGY/PRINCIPAL FINDINGS: In this manuscript, we have characterized the ability of CD40-activated B cells, stimulated or not with Toll-like receptor (TLR) agonists (CpG or lipopolysaccharide) to induce the response of mouse naïve CD8(+) T cells in vivo. Our results show that CD40-activated B cells can directly present antigen to naïve CD8(+) T cells to induce the generation of potent effectors able to secrete cytokines, kill target cells and control a Listeria monocytogenes infection. However, CD40-activated B cell immunization did not lead to the proper formation of CD8(+) memory T cells and further maturation of CD40-activated B cells with TLR agonists did not promote the development of CD8(+) memory T cells. Our results also suggest that inefficient generation of CD8(+) memory T cells with CD40-activated B cell immunization is a consequence of reduced Bcl-6 expression by effectors and enhanced contraction of the CD8(+) T cell response. CONCLUSIONS: Understanding why CD40-activated B cell immunization is defective for the generation of memory T cells and gaining new insights about signals that should be provided by APCs are key steps before translating the use of CD40-B cell for therapeutic vaccination.

Melanin-concentrating hormone induces neurite outgrowth in human neuroblastoma SH-SY5Y cells through p53 and MAPKinase signaling pathways.

Melanin-concentrating hormone (MCH) peptide plays a major role in energy homeostasis regulation. Little is known about cellular functions engaged by endogenous MCH receptor (MCH-R1). Here, MCH-R1 mRNA and cognate protein were found expressed in human neuroblastoma SH-SY5Y cells. Electrophysiological experiments demonstrated that MCH modulated K(+) currents, an effect depending upon the time of cellular growth. MCH treatments induced a transient phosphorylation of MAPKinases, abolished by PD98059, and partially blocked by PTX, suggesting a Galphai/Galphao protein contribution. MCH stimulated expression and likely nuclear localization of phosphorylated p53 proteins, an effect fully dependent upon MAPKinase activities. MCH treatment also increased phosphorylation of Elk-1 and up-regulated Egr-1, two transcriptional factors targeted by the MAPKinase pathway. Finally, MCH provoked neurite outgrowth after 24h-treatment of neuroblastoma cells. This effect and transcriptional factors activation were partly prevented by PD98059. Collectively, our results provide the first evidence for a role of MCH in neuronal differentiation of endogenously MCH-R1-expressing cells via non-exclusive MAPKinase and p53 signaling pathways.