Department of Microbiology, Molecular Genetics, and Immunology
Ph.D., Purdue University, 1999
Pharm.D., University of Illinois at Chicago, 1995
Fellowship, University of Washington, 1999-2004
T cell homeostasis is critical for maintaining the balance between immune competency, autoimmunity, and malignancy. To maintain a steady state number of T cells, we need to continuously produce new T cells to offset the number of T cells that die or differentiate. Our research is focused on the signaling pathways that regulate T cell development and activation. In particular, we study an adaptor protein called Gads and seek to understand the biochemical and biological functions of Gads.
Gads consists of an N-terminal SH3 domain, an SH2 domain, a linker region, and a C-terminal SH3 domain. The SH2 and C-terminal SH3 domains bind LAT and SLP-76, respectively. The formation of the LAT/Gads/SLP-76 complex is required for TCR-mediated calcium mobilization. Whether Gads regulates other signaling pathways is currently unknown. In addition, the functions of the N-terminal SH3 domain and the linker region are unclear. Gads can also be phosphorylated, but the biological function of this phosphorylation is unclear.
The biological functions of Gads can be divided into two areas: T cell development and T cell activation. T cell development is an ordered series of stages that culminates in the generation of a diverse T cell repertoire with limited ability to recognize self-antigens. Gads is required for the two stages of T cell development that correspond to the stages at which the two chains of the T cell receptor are generated. Defects in these stages can lead to immune deficiency or autoimmune disease. The second area of interest is T cell activation. Although Gads appears to have the same biochemical function in CD4+ T cells and CD8+ T cells, the biological effects of Gads-deficiency are different in these populations. CD4+ T cells fail to survive without Gads while CD8+ T cells are only mildly impaired without Gads. Using an infection model, we showed that Gads is required for optimal expansion of CD8+ T cells, but not for the differentiation of CD8+ T cells into effector or memory cells.
Yankee, T.M., Draves, K.E., Ewings, M.K., Clark, E.A., and Graves, J.D. (2001) CD95/Fas induces cleavage of the GrpL/Gads adaptor and desensitization of antigen receptor signaling. Proc. Natl. Acad. Sci., 98: 6789-93.
Yankee, T.M., Solow, S., Draves, K.E., and Clark, E.A. (2003) Expression of the Grb2-Related Protein of the Lymphoid System/Gads adapter protein in B cell subsets enhances B cell antigen receptor signaling through Mitogen-Activated Protein Kinase pathways. J. Immunol. 170:349-55.
Yankee, T.M., Yun, T.J., Draves, K.E., Ganesh, K., Bevan M.J., Kaja, M.K., and Clark E.A. (2004) The Gads (GrpL) adaptor protein regulates T cell homeostasis. J. Immunol. 173: 1711-20.
Yankee, T.M., Draves, K.E., and Clark, E.A. (2005) Expression and function of the Gads adaptor protein in murine B cells. Eur. J. Immunol., 35: 1184-82.
Zeng, L., Dalheimer, S.L., and Yankee, T.M. (2007) Gads-/- Mice Reveal Functionally Distinct Subsets of TCRbeta+ CD4-CD8- Double-Negative Thymocytes. J. Immunol. 179: 1013-21.
Dalheimer, S.D., Zeng, L., Draves, K.E., Jiwa, N.N., Parrish, T.D., Clark, E.A., and Yankee, T.M. (2009) Gads-deficient thymocytes are blocked at the transitional single positive CD4+ stage. Eur. J. Immunol., 39: 1395.
Taglauer, E.G., Yankee, T.M., and Petroff, M.G. (2009) Maternal PD-1 Regulates Accumulation of Paternal Antigen-Specific CD8+ T cells in Pregnancy. J. Reprod. Immunol., 80: 12.
Xiong J, Armato MA, Yankee TM. (2011) Immature single-positive CD8+ thymocytes represent the transition from Notch-dependent to Notch-independent T-cell development. Int. Immunol., 23: 55-64.
Zhang E.Y., Parker, B.L., and Yankee T.M. (2011) Gads regulates the kinetics of CD8+ T cell activation and proliferation. J. Immunol. 186: 4579-89.
Zhang, E.Y., Parker, B.L., Xiong, J., Chen, A.Y., Qiu, J., Ma, X., and Yankee, T.M. (2011) Depletion and recovery of lymphoid subsets following morphine administration. Brit. J. Pharmocol., 164: 1829-44.
Thomas M. Yankee, Pharm.D., Ph.D.