CXCR4 Chemokine Receptor Regulation of ERK MAP Kinase

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DESCRIPTION (provided by applicant): T lymphocyte activation and migration are critical for normal immune functions. Signaling by both the T lymphocyte antigen receptor-CD3 complex (TCR) and chemokine receptors such as CXCR4 are extensively cross-regulated, however, until recently little was known about the molecular mechanisms responsible for this cross-regulation. Moreover, although CXCR4 is ubiquitously-expressed, highly conserved, and essential for Human Immunodeficiency Virus-1 (HIV-1) infection of T cells, few specific immune function(s) of T lymphocyte CXCR4 have been proposed. The CXCR4 ligand, SDF-1, is constitutively expressed at specific anatomic sites, include the bone marrow, lymph nodes, and gut. SDF-1/CXCR4 signaling on T cells may, therefore, critically modulate T cell immune activation in these locations. Our results during the last cycle of this grant (recently published in Immunity) indicate that SDF-1 stimulation of CXCR4 produces signals in T cells via a novel mechanism: by inducing the formation of CXCR4/TCR complexes which then utilize the TCR ITAM domains and TCR-associated signaling molecules to activate the Ras/ERK MAP kinase pathway. Our preliminary results further indicate that this pathway mobilizes AP-1-dependent transcription factors that are responsible for SDF-1 co-stimulation of IL-10 production and secretion by T cells. Experiments proposed below are designed to further characterize three key areas of this novel signaling pathway. Aims 1 & 2 will test the central hypothesis that SDF-1 stimulates .the formation of CXCR4/TCR complexes by enhancing the trafficking of CXCR4 into late recycling endosomes that also contain constitutively-recycling TCR molecules, and that the clumping of these vesicles near the MTOC and Golgi permits CXCR4/TCR complexes to signal via Ras-ERK pathway components on the endosomes and/or Golgi. Aim 3 will test the related hypothesis that this signaling pathway enhances T cell secretion of IL-10 and thereby critically modulates immunity. Together, the results of the proposed studies will characterize key points of the recently-discovered novel mechanism by which CXCR4 signals in T cells, and that may also participate in CXCR4-mediated migration, integrin regulation and HIV-1 pathobiology. In addition, the results of the proposed studies will delineate the importance of this pathway for CXCR4 co-stimulation of T cell IL-10 secretion and immune regulation, results that have the potential improve therapies of human autoimmune diseases that depend on IL-10.