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Principal Investigator: JULIE ZIKHERMAN
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $403,750
Funding agency: National Institute of Allergy and Infectious Diseases
CD28 is a T cell surface molecule that can provide a second signal, when combined with immobilized TCR
ligands, to induce naïve T activation. Costimulation results from the interaction of CD28 with its ligands CD80
(B7.1) and CD86 (B7.2) induced on activated antigen-presenting cells by activation of the innate immune
system. We do not have a good molecular understanding of how CD28 mediates its costimulatory signals.
Models and experimental evidence have suggested that CD28 either: 1) augments the magnitude of TCR
signaling; or, 2) provides a unique signal, qualitatively distinct from that provided by the TCR. It is important to
understand the molecular signaling pathways underlying costimulation since interrupting costimulation has
been important clinically. A deeper insight into CD28 signaling pathways may enable the development of new
therapeutics that would be useful in blocking the immune system. Very recent studies from my lab provide
some new insights and suggest approaches and clues that will enable us identify previously unrecognized
components of the CD28-regulated signaling pathways and permit a more complete understanding of CD28
signaling. These chemical-biology, genetic and proteomic studies lead us to hypothesize that an important
consequence of CD28 costimulation is the regulation of the actin cytoskeleton and this influences
signals downstream of the TCR. We will explore this via the following specific aims: 1) Determine the
mechanism by which costimulation modulates the actin cytoskeleton to facilitate PLCγ1 mediated hydrolysis of
PIP2 in double positive (CD4+CD8+, DP) thymocytes and in more mature T cells; 2) Determine how CD28
overcomes a negative regulatory influence of Pyk2 and Cbl-b on T cell signaling leading to IL-2 production and
T cell proliferation; and, 3) Using recently obtained phosphoproteomic data, we will identify key components of
the pathway downstream of CD28 and those that modulate the actin cytoskeleton in response to CD28
costimulation.
Terms: <1-Phosphatidylinositol 3-Kinase><280 kDa actin-binding protein><Actins><Adhesions><Affect><Antigen-Presenting Cells><Antigens><Autoimmune Status><Autoimmunity><Awareness><B7-1><BB1><Biochemical><Biology><CD28><CD28 Antigens><CD28 gene><CD28 molecule><CD28LG><CD28LG1><CD3><CD3 Antigens><CD3 Complex><CD3 molecule><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD80><CD80 gene><CD86><CD86 gene><CD8B><CD8B1><CD8B1 gene><Cancers><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Signaling><Cell surface><Cell-to-Cell Interaction><Cells><Cellular Matrix><Chemicals><Clinical><Clinical Treatment Moab><Co-Stimulator><Collaborations><Costimulator><Cytoplasm><Cytoplasmic Domain><Cytoplasmic Tail><Cytoskeletal System><Cytoskeleton><Data><Dendritic Cells><Development><EPH- and ELK-Related Tyrosine Kinase><EPH-and ELK-Related Kinase><Elements><Ensure><Ephrin Type-A Receptor 8><Ephrin Type-A Receptor 8 Precursor><Epidermal Thymocyte Activating Factor><FADK><FAK><FAK1><Genetic><Hydrolysis><ICAM><IL-2><IL2 Protein><Immobilization><Immune response><Immune system><Immunological response><Infection><Innate Immune System><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Interruption><Intracellular Communication and Signaling><Kinases><LAB7><LYT3><Lecithinases><Ligands><Lymphocyte Mitogenic Factor><MHC Receptor><Major Histocompatibility Complex Receptor><Malignant Neoplasms><Malignant Tumor><Mature T-Cell><Mature T-Lymphocyte><Mediating><Mice><Mice Mammals><Mitogenic Factor><Modeling><Molecular><Monoclonal Antibodies><Murine><Mus><Names><OKT3 antigen><PI-3 Kinase><PI3-Kinase><PI3CG><PI3KGamma><PI3k><PIK3><PIK3CG><PIK3CG gene><PIP2><PLC gamma1><PLC-γ1><PLCγ1><PTK2><PTK2 gene><Pathologic><Pathway interactions><Phosphatidylinositol 3-Kinase><Phosphatidylinositol 4,5-Biphosphate><Phosphatidylinositol 4,5-Diphosphate><Phosphatidylinositol-3-OH Kinase><Phosphatidylinositol-4,5-Bisphosphate><Phosphoinositide 3-Hydroxykinase><Phospholipase><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Production><Protein Phosphorylation><Protein Tyrosine Kinase><Protein Tyrosine Kinase EEK><Proteins><Proteomics><PtIns 4,5-P2><PtdIns 3-Kinase><PtdInsP2><Recombinants><Regulation><Serine Phosphorylation Site><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Superantigens><T cell growth factor><T cell response><T-Cell Activation><T-Cell Antigen CD28><T-Cell Antigen Receptors><T-Cell Growth Factor><T-Cell Proliferation><T-Cell Receptor><T-Cell Stimulating Factor><T-Cells><T-Lymphocyte><T3 Antigens><T3 Complex><T3 molecule><T4 Cells><T4 Lymphocytes><T44><T8 Cells><T8 Lymphocytes><T90/44><Therapeutic><Threonine Phosphorylation Site><Thymocyte Stimulating Factor><Tp44><Transphosphorylases><Transplantation><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><Tyrosine Kinase><Tyrosine Phosphorylation><Tyrosine Phosphorylation Site><Tyrosine-Protein Kinase Receptor EEK><Tyrosine-Specific Protein Kinase><Tyrosylprotein Kinase><Veiled Cells><accessory cell><activate T cells><biological signal transduction><design><designing><developmental><filamin><filamin 1><filamin A><host response><hydroxyaryl protein kinase><immune system response><immunogen><immunoresponse><inhibitor><insight><intercellular cell adhesion molecule><intracellular skeleton><kinase inhibitor><mAbs><malignancy><monoclonal Abs><mutant><name><named><naming><neoplasm/cancer><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><orthopedic freezing><pathogen><pathway><phospho-proteomics><phospholipase C gamma 1><phospholipase C gamma1><phospholipase C-γ1><phospholipase Cγ1><phosphoproteomics><polyproline><pp125FAK><recruit><response><rho G-Proteins><rho GTP-Binding Proteins><rho GTPases><rho Protein P21><rho Small GTP-Binding Proteins><small molecular inhibitor><small molecule inhibitor><src Kinases><src Protein-Tyrosine Kinases><src Tyrosine Kinases><src-Family Kinases><src-Family Tyrosine Kinases><thymocyte><thymus derived lymphocyte><transplant><tyrosyl protein kinase>