Our laboratory studies signal transduction involving tyrosine phosphorylation and non-receptor tyrosine kinases, molecules required for intracellular signaling pathways involved in normal cellular growth and differentiation as well as the abnormal growth and development involved in the formation and progression of cancer. Using a combination of genetics, cell biology and protein biochemistry, our work has concentrated on how these molecules contribute to normal function of cells in the immune system. Through these studies we hope to understand how manipulation of these pathways can be utlilized to develop therapeutics for disease. In recent years our work has concentrated on studies of the Tec family of tyrosine kinases, the prototypical member of which, Btk, is required for normal function of B cells. Mutation of Btk is responsible for the human genetic disorder X-linked agammmaglobulimemia. We have shown that mutation of Tec family kinases expressed in T cells can also severely impair T lymphocyte function in mice and has profound effects on responses to infections in vivo. In the last year, we have concentrated on biochemical defects associated with mutation of the Tec kinases in T lymphocytes. Previous studies have demonstrated that the Tec kinases are critical for antigen receptor induced activation of phospholipase-c gamma, a key enzyme required for Ca++ mobilization. We have now found that mutation of Tec kinases also impairs actin cytoskeletal reorganization and activation of WASP, the protein mutated in Wiskott-Aldrich Syndrome, a syndrome associated with defective cytoskeleton organization. We have further shown that the defect in WASP activation is secondary to altered activation of Cdc42, a Rho family GTPase and altered subcellular localization of the guanine nucleotide exchange factor Vav. Moreover, we have found that cells deficient in Tec kinases also show abnormal responses to chemokines, small molecules that direct cell polarization and cell trafficking in the immune system. Our results place the Tec kinases as critical regulators of the actin cytoskeleton, cell adhesion and migration and suggest that cytoskeletal defects may contribute to the phenotypes associated with Tec kinase deficiency including those seen in X-linked agammaglobulinemia. In continuing work, we are also examining the effects of mutation of Tec kinases on T cell responses in vivo. We had previously found that mutation of the Tec kinases alters the balance of T helper cell differentiation and cytokine production. As an extension of these studies, we began examining other signaling molecules potentially involved in T helper cell differentiation including SAP, which is mutated in the genetic disorder X-linked proliferative syndrome (XLP). We had previously generated mice deficient in SAP and have found that upon challenge with infectious agents, these mice recapitulated features of XLP, including increased T cell activation and IFN-g production, a Th1 response, and decreased antibody production. Last year, we showed that the impaired antibody response in these mice was secondary to a defect in CD4+ T cells, ie SAP deficient T cells fail to provide an essential signal to B cells for generating long-term antibody responses, a critical step for the development of successful immunization and immune responses. The ability to develop a sustained antibody response is a hallmark of productive immunity and a standard for successful vaccine development. Thus, understanding the cellular interactions and signals leading to productive immunization is of high importance. To understand the defect in T cells in the Sap-deficient mice, we have examined T cell function, cytokine production and biochemistry of T cell activation in cells from SAP-deficient mice. We have found that T cells from Sap deficient mice show increased Th1 cytokine production (IFN-g) and dramatic defects in Th2 cytokine production (IL-4, 5, and 10) in response to TCR stimulation. Given the role of Th2 cytokines in promoting B cell help for antibody production, the defect in Th2 cytokine production provides new insights into the mechanism of disease in XLP. We have further examined T cell activation and have found that SAP-deficient cells show defective activation of the NFKB transcription factor. These studies are revealing a new pathway for the regulation of T helper cell differentiation via NFKB. Furthermore, our results suggest that T helper cell misregulation may contribute to phenotypes associated with XLP.
| Chiang, Y Jeffrey; Jordan, Martha S; Horai, Reiko et al. (2009) Cbl enforces an SLP76-dependent signaling pathway for T cell differentiation. J Biol Chem 284:4429-38 |
| Schwartzberg, Pamela L; Mueller, Kristen L; Qi, Hai et al. (2009) SLAM receptors and SAP influence lymphocyte interactions, development and function. Nat Rev Immunol 9:39-46 |
| Steinfelder, Svenja; Andersen, John F; Cannons, Jennifer L et al. (2009) The major component in schistosome eggs responsible for conditioning dendritic cells for Th2 polarization is a T2 ribonuclease (omega-1). J Exp Med 206:1681-90 |
| Linterman, Michelle A; Rigby, Robert J; Wong, Raphael K et al. (2009) Follicular helper T cells are required for systemic autoimmunity. J Exp Med 206:561-76 |
| Sahu, Nisebita; Venegas, Ana M; Jankovic, Dragana et al. (2008) Selective expression rather than specific function of Txk and Itk regulate Th1 and Th2 responses. J Immunol 181:6125-31 |
| Readinger, Julie A; Schiralli, Gillian M; Jiang, Jian-Kang et al. (2008) Selective targeting of ITK blocks multiple steps of HIV replication. Proc Natl Acad Sci U S A 105:6684-9 |
| Schwartzberg, Pamela L (2007) Formin the way. Immunity 26:139-41 |
| Konno, Akihiro; Kirby, Martha; Anderson, Stacie A et al. (2007) The expression of Wiskott-Aldrich syndrome protein (WASP) is dependent on WASP-interacting protein (WIP). Int Immunol 19:185-92 |
| Zhao, Ling; Cannons, Jennifer L; Anderson, Stacie et al. (2007) CBFB-MYH11 hinders early T-cell development and induces massive cell death in the thymus. Blood 109:3432-40 |
| Gomez-Rodriguez, Julio; Readinger, Julie A; Viorritto, Irene C et al. (2007) Tec kinases, actin, and cell adhesion. Immunol Rev 218:45-64 |
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