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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059763-11
Application #
7778322
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Marino, Pamela
Project Start
1999-09-30
Project End
2011-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
11
Fiscal Year
2010
Total Cost
$290,110
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Kremer, Kimberly N; Dinkel, Brittney A; Sterner, Rosalie M et al. (2017) TCR-CXCR4 signaling stabilizes cytokine mRNA transcripts via a PREX1-Rac1 pathway: implications for CTCL. Blood 130:982-994
Bamidele, Adebowale O; Kremer, Kimberly N; Hirsova, Petra et al. (2015) IQGAP1 promotes CXCR4 chemokine receptor function and trafficking via EEA-1+ endosomes. J Cell Biol 210:257-72
Erskine, Courtney L; Krco, Christopher J; Hedin, Karen E et al. (2011) MHC class II epitope nesting modulates dendritic cell function and improves generation of antigen-specific CD4 helper T cells. J Immunol 187:316-24
Kremer, Kimberly N; Kumar, Ashok; Hedin, Karen E (2011) G alpha i2 and ZAP-70 mediate RasGRP1 membrane localization and activation of SDF-1-induced T cell functions. J Immunol 187:3177-85
Kremer, Kimberly N; Clift, Ian C; Miamen, Alexander G et al. (2011) Stromal cell-derived factor-1 signaling via the CXCR4-TCR heterodimer requires phospholipase C-?3 and phospholipase C-?1 for distinct cellular responses. J Immunol 187:1440-7
Kumar, Ashok; Kremer, Kimberly N; Dominguez, Daniel et al. (2011) Gýý13 and Rho mediate endosomal trafficking of CXCR4 into Rab11+ vesicles upon stromal cell-derived factor-1 stimulation. J Immunol 186:951-8
Kumar, Ashok; Kremer, Kimberly N; Sims, Olivia L et al. (2009) Measuring the proximity of T-lymphocyte CXCR4 and TCR by fluorescence resonance energy transfer (FRET). Methods Enzymol 460:379-97
Kremer, Kimberly N; Kumar, Ashok; Hedin, Karen E (2007) Haplotype-independent costimulation of IL-10 secretion by SDF-1/CXCL12 proceeds via AP-1 binding to the human IL-10 promoter. J Immunol 178:1581-8
Kumar, Ashok; Humphreys, Troy D; Kremer, Kimberly N et al. (2006) CXCR4 physically associates with the T cell receptor to signal in T cells. Immunity 25:213-24
Billadeau, Daniel D; Chatterjee, Subrha; Bramati, Patricia et al. (2006) Characterization of the CXCR4 signaling in pancreatic cancer cells. Int J Gastrointest Cancer 37:110-9

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