RESUMEN
CD27 is a lymphocyte-specific member of the TNF receptor (TNFR) family. It is a costimulatory molecule for peripheral T cells, as defined by its ability to enhance the TCR-induced proliferative response. We show here that CD27 augments TCR-induced Jun N-terminal kinase (JNK) activity in primary murine lymph node T cells. To investigate how CD27 couples to JNK, we performed a yeast two hybrid screen with the CD27 cytoplasmic tail. This revealed that CD27 directly associates with Traf-2. Transfection experiments using dominant negative Traf-2 indicated that CD27 communicates with JNK via Traf-2. These findings group CD27 together with other members of the TNFR family, TNFR-1, -2, CD30 and CD40, which have all been shown to couple to Traf proteins. Since Traf proteins have been reported to initiate an anti-apoptotic signaling pathway, our data suggest that CD27 not only regulates proliferation, but also survival of T lymphocytes.
Asunto(s)
Proteínas Quinasas JNK Activadas por Mitógenos , Quinasas de Proteína Quinasa Activadas por Mitógenos , Proteínas Quinasas/fisiología , Proteínas/fisiología , Receptores del Factor de Necrosis Tumoral/fisiología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/fisiología , Animales , Apoptosis , Células COS , MAP Quinasa Quinasa 4 , Ratones , Ratones Endogámicos C57BL , Linfocitos T/fisiología , Factor 2 Asociado a Receptor de TNFRESUMEN
Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an important regulator of T cell homeostasis. Ligation of this receptor leads to prominent downregulation of T cell proliferation, mainly as a consequence of interference with IL-2 production. We here report that CTLA-4 engagement strikingly selectively shuts off activation of downstream T cell receptor (TCR)/CD28 signaling events, i.e., activation of the microtubule-associated protein kinase (MAPKs) ERK and JNK. In sharp contrast, proximal TCR signaling events such as ZAP70 and TCR-zeta chain phosphorylation are not affected by CTLA-4 engagement on activated T cells. Since activation of the ERK and JNK kinases is required for stimulation of interleukin (IL)-2 transcription, these data provide a molecular explanation for the block in IL-2 production imposed by CTLA-4.
Asunto(s)
Antígenos de Diferenciación/fisiología , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Inmunoconjugados , Proteínas de la Membrana/metabolismo , Proteínas Quinasas Activadas por Mitógenos , Proteínas Tirosina Quinasas/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T Citotóxicos/inmunología , Abatacept , Animales , Antígenos CD , Antígenos de Diferenciación/metabolismo , Antígeno CTLA-4 , Proteínas Quinasas Dependientes de Calcio-Calmodulina/inmunología , Activación Enzimática/inmunología , Interleucina-2/genética , Proteínas Quinasas JNK Activadas por Mitógenos , Proteínas de la Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Fosforilación , Proteínas Tirosina Quinasas/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Transcripción Genética/inmunología , Proteína Tirosina Quinasa ZAP-70RESUMEN
We recently described an mAb (MTS23) reactive with a membrane Ag expressed on a subset of thymic medullary stromal cells. This Ag is also constitutively expressed at high levels on peripheral B cells, macrophages, and thymic and splenic dendritic cells of C57BL/6 mice. A number of stromal cell lines derived from thymus and bone marrow also stain with MTS23, but thymocytes and peripheral T cells only weakly express the Ag detected by MTS23. Here we show that the molecule detected by MTS23 is a member of the Ly-6 family of phosphatidylinositol-anchored membrane proteins. Treatment of stromal cells with phosphatidylinositol-phospholipase C before staining completely abolished expression. Using transient expression of 293T cells and a cDNA library of a stromal cell line cloned into the pEF-BOS vector, a cDNA encoding the MTS23-target Ag was isolated. Partial sequencing and restriction enzyme mapping revealed that it represents the Ly-6A/E protein. While the physiologic significance of the presence of Ly-6 molecules on stromal cells is not clear, it has been known for some time that, at least in lymphocytes, cellular activation events can be induced upon Ly-6 engagement. We now demonstrate that Ly-6 also functions as a signal transduction molecule on stromal cells, in that granulocyte-macrophage CSF can be produced by a variety of stromal cell lines upon mAb-mediated cross-linking of Ly-6. Together with the dramatic up-regulation of Ly-6 expression on stromal cells upon IFN-gamma treatment, this is the first indication of a biologic function of an Ly-6 gene product on nonhemopoietic cells. The results suggest that Ly-6 may play a role in the cross-talk between lymphocyte precursors and stromal cells.