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 mouse genetics, cell biology and protein biochemistry, our work has concentrated on how these molecules contribute to normal function of cells of the immune system and the skeletal system. Through these studies we hope to understand how manipulation of these pathways can be utlilized to develop therapeutics for diseases affecting these systems. 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 previously shown that mutation of Tec family kinases expressed in T cells can severely impair T lymphocyte function in mice, thereby establishing for the first time a role for these kinases in T cell mediated immune responses. In the last year our work has concentrated on how these kinases participate in the signaling pathways involved in T helper cell differentiation, a critical regulatory component of immune responses that helps determine whether an individual mounts a cellular (Th1) or antibody based, (Th2) immune response. We have found that mutation of Tec kinases can alter activation and repression of transcription factors involved in Th2 CD4+ T helper cell differentiation. Our results suggest that impairment of TCR responses may not only reduce the ability of an animal to respond to antigen, but may also alter the type of immune response generated. 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). In this last year we have generated mice deficient in SAP. SAP-deficient mice had normal lymphocyte development, but upon challenge with infectious agents, recapitulated features of XLP, including increased T cell activation and IFN-g production, and decreased antibody production. Splenocytes from uninfected SAP- mice produced increased IFN-g and decreased IL-4, suggesting a skewing of these animals to a Th1 phenotype. Our results suggest that T helper cell misregulation may contribute to phenotypes associated with (XLP).
| 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 |
| 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 |
| 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 |
| Gomez-Rodriguez, Julio; Readinger, Julie A; Viorritto, Irene C et al. (2007) Tec kinases, actin, and cell adhesion. Immunol Rev 218:45-64 |
| Adriani, Marsilio; Aoki, Joseph; Horai, Reiko et al. (2007) Impaired in vitro regulatory T cell function associated with Wiskott-Aldrich syndrome. Clin Immunol 124:41-8 |
| Horai, Reiko; Mueller, Kristen L; Handon, Robin A et al. (2007) Requirements for selection of conventional and innate T lymphocyte lineages. Immunity 27:775-85 |
| Kim, In-Jeong; Burkum, Claire E; Cookenham, Tres et al. (2007) Perturbation of B cell activation in SLAM-associated protein-deficient mice is associated with changes in gammaherpesvirus latency reservoirs. J Immunol 178:1692-701 |
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