for our requested R37 Extension is modified slightly from the abstract of our last competitiverenewal to reflect our recent progress)The overall goal of this proposal is to examine various aspects of how the SLP-76 adapter moleculefunctions during T cell development and in mature T cell function. Prior work from our group identified SLP-76 as a key molecule necessary for signaling downstream ofthe pre-T cell receptor and T cell receptor.Complete loss of SLP-76 expression due to targeted deletion in a murine model system results in failedthymocyte development early in ontogeny (at the double negative three [DNS] stage). Recent work from ourlaboratory has resulted in the generation of mice in which the SLP-76 gene was flanked by loxP sites toallow for both lineage specific and temporally controlled deletion ofthe gene. Additionally, in the past threeyears, we have generated three knock-in mutations of the SLP-76 gene to address the role of this adapterprotein in T cell develoment and function. Using these novel genetic tools, three specific aims are proposed.
The first aim will be to analyze the impact of specific tyrosine mutations of SLP-76 on CD4+ and CD8+ T celleffector and memory functions.
The second aim will probe the mechanisms through which SLP-76 functionsby examining the intermolecular interactions mediated by wild type SLP-76 versus the SLP-76 mutantproteins. These studies will provide new insights into how various molecular interactions control the keysignaling events that are initiated by T cell receptor engagement and how these signals are translated intoeffector functions. The third specific aim of this proposal will continue to test the importance of SLP-76relocalization for immune cell function. For these experiments we will generate additional SLP-76 mutantsthat alter its location within the cell. Finally, we propose a fourth pilot aim. In these studies we will performthe initial characterization of a previously undescribed cDNA that encodes a molecule with apparenthomology to SLP-76.
In recent years, it has become clear that adapter proteins play as critical role as receptors, enzymes, andtranscription factors in the regulation of signal transduction after cell surface receptors are engaged. Thestudies described in this proposal dissect the molecular mechanisms by which one such adapter, SLP-76,functions in T cells. Understanding how this molecule integrates signaling pathways will provide newinsights into ways by which immune cell function can be modulated for therapeutic advantage.
|Carty, Shannon A; Koretzky, Gary A; Jordan, Martha S (2014) Interleukin-4 regulates eomesodermin in CD8+ T cell development and differentiation. PLoS One 9:e106659|
|Kim, Jiyeon S; Sklarz, Tammarah; Banks, Lauren B et al. (2013) Natural and inducible TH17 cells are regulated differently by Akt and mTOR pathways. Nat Immunol 14:611-8|
|Kim, Jiyeon S; Smith-Garvin, Jennifer E; Koretzky, Gary A et al. (2011) The requirements for natural Th17 cell development are distinct from those of conventional Th17 cells. J Exp Med 208:2201-7|
|Chang, John T; Ciocca, Maria L; Kinjyo, Ichiko et al. (2011) Asymmetric proteasome segregation as a mechanism for unequal partitioning of the transcription factor T-bet during T lymphocyte division. Immunity 34:492-504|
|Smith-Garvin, Jennifer E; Burns, Jeremy C; Gohil, Mercy et al. (2010) T-cell receptor signals direct the composition and function of the memory CD8+ T-cell pool. Blood 116:5548-59|
|Zou, Tao; May, Rebecca M; Koretzky, Gary A (2010) Understanding signal integration through targeted mutations of an adapter protein. FEBS Lett 584:4901-9|
|Sonnenberg, Gregory F; Mangan, Paul R; Bezman, Natalie A et al. (2010) Mislocalization of SLP-76 leads to aberrant inflammatory cytokine and autoantibody production. Blood 115:2186-95|
|Bezman, Natalie A; Baker, Rebecca G; Lenox, Laurie E et al. (2009) Cutting edge: rescue of pre-TCR but not mature TCR signaling in mice expressing membrane-targeted SLP-76. J Immunol 182:5183-7|
|Hunter, A J; Ottoson, N; Boerth, N et al. (2000) Cutting edge: a novel function for the SLAP-130/FYB adapter protein in beta 1 integrin signaling and T lymphocyte migration. J Immunol 164:1143-7|
|Boerth, N J; Sadler, J J; Bauer, D E et al. (2000) Recruitment of SLP-76 to the membrane and glycolipid-enriched membrane microdomains replaces the requirement for linker for activation of T cells in T cell receptor signaling. J Exp Med 192:1047-58|
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