Immunology, Apoptosis, Signal Transduction, T cells, Autoimmunity, Cancer Biology
University of California, San Diego
Postdoctoral Mentor - Stephen M. Hedrick, Ph.D.
Our research focuses on the role apoptotic signal transduction plays in the development, activation and homeostasis of the immune system. Our current interests include the study of death-receptors and the regulation of T cell activation. In order to study the role of death-receptor induced apoptosis in T cells, we have generated mice that express inhibitors of certain apoptotic pathways. One line of mice expresses a dominant-negative form of an adapter molecule known as FADD. This adapter protein is involved in activating caspases, cysteine proteases that initiate and execute the death program during apoptosis. Although certain forms of apoptosis are blocked, these and other lines of transgenic mice have provided evidence that multiple apoptotic pathways exist in T cells that are activated during different stages of differentiation. Interestingly, we have found that FADD mutant T cells have defective proliferative responses to normal mitogenic stimulation. Thus, a major focus has been to elucidate the biochemical basis for this proliferative defect. These paradoxical results suggest that T cells utilize similar signal transduction pathways to initiate proliferation and apoptosis and provide a framework for elucidating the homeostatic regulation of T cells that is crucial for a functional immune system. A second area of investigation regards the signal transduction pathways that regulate the elimination of autoreactive T cells during thymocyte differentiation, a developmental process known as negative selection. Since this stage is thought to involve apoptosis, we are investigating apoptotic pathways that might contribute to this process. More recently, we have extended our focus to the mechanisms that prevent self-recognition in the peripheral immune system as well. This work is of high significance to our understanding of immunological tolerance, the means by which the adaptive immune system avoids self-recognition and autoimmunity. During the course of this research, we have identified a novel serine-threonine kinase called DRAK2 that is differentially regulated during thymocyte development. We have found that this kinase plays a role in regulating thymocyte development and alters the signaling threshold in peripheral T cells. Despite hyper-responsive T cells, mice with an engineered deficiency in DRAK2 are enigmatically resistant to spontaneous and induced autoimmune diseases. Although the specific function of this kinase is unclear, our lab is currently investigating the role of this kinase in T cell development and activation. Ultimately, our objective is to investigate the paradigms that regulate immune homeostasis through the study of the intersection of apoptotic and growth regulatory pathways.A third area of investigation is on the interaction between T cells and neural stem cells, with the hypothesis that T cell tolerance is essential for the successful transplantation of stem cell derivatives. Our work focuses on both viral- and myelin antigen-induced models of multiple sclerosis (MS), and seeks to define specific strategies to promote immune tolerance to stem cell derivatives following transplantation to treat MS.
Weinger J.L., Plaisted W.C., Maciejewski S.M., Lanier L.L., Walsh C.M., Lane T.E. 2014. Activating Receptor NKG2D Targets RAE-1-Expressing Allogeneic Neural Precursor Cells in a Viral Model of Multiple Sclerosis. Stem Cells, In Press.
Chen L., Coleman R., Leang R., Tran H., Kopf A., Walsh C.M., Sears-Kraxberger I., Steward O., Macklin W.B., Loring J.F., Lane T.E. 2014. Human neural precursor cells promote neurologic recovery in a viral model of multiple sclerosis. Stem Cell Reports. 2014 May 15;2(6):825-37. doi: 10.1016/j.stemcr.2014.04.005. eCollection 2014 Jun 3.
Salvesen G.S. and Walsh C.M. 2014. Functions of Caspase 8: the Identified and the Mysterious. Semin Immunol. 2014 May 21. pii: S1044-5323(14)00046-3. doi: 10.1016/j.smim.2014.03.005. [Epub ahead of print]
Walsh C.M. 2014. Grand Challenges in Cell Death and Survival: Apoptosis vs. Necroptosis. Front. Cell and Developmental Biology 2(3):1- 4.
Plaisted W.C., Walsh C.M., Lane T.E. 2014. T Cell Mediated Suppression of Neurotropic Coronavirus Replication in Neural Precursor Cells. Virology 449:235-243.
Fracchia K.M., Pai C., Walsh C.M. 2013. Modulation of T cell metabolism and function through calcium signaling. Front. Immunol., 11(4;324): 1-17.
Klionsky D.J., …. Walsh C.M., … Zuckerbraun B. 2012. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 6: 445-544.
Lu J.V., Walsh C.M. 2012. Programmed necrosis and autophagy in immune function.
Immunological Reviews, 249(1): 205-17.
Yang K.M., Kim W., Bae E.J., Gim J.S., Weist B.M., Jung Y.S., Hyun J.S., Hernandez J.B., Leem S.H., Park T.S., Jeong J., Walsh C.M., and Kim S.J. 2012. DRAK2 Participates in a Negative Feedback Loop to Control TGF-beta/Smads Signaling by Binding to Type I TGF-beta Receptor. Cell Reports, in press.
Weist B.M., Hernandez J.B., Walsh C.M. 2012. Loss of DRAK2 signaling enhances allogeneic transplant survival by limiting effector and memory T cell responses. American Journal of Transplantation 12(8):2220-7.
Weinger J.G., Weist B.M., Plaisted W.C., Klaus S.M., Walsh C.M., Lane T.E. 2012. MHC mismatch results in neural progenitor cell rejection following spinal cord transplantation in a model of viral-induced demyelination. Stem Cells 30(11): 2584–2595
Lu J.V., Weist B.M., van Raam B.J., Marro B.S., Nguyen L.V., Srinivas P., Bell B.D., Luhrs K.A., Lane T.E., Salvesen G.S., Walsh C.M. 2011. Complementary roles of Fas-associated death domain (FADD) and receptor interacting protein kinase-3 (RIPK3) in T cell homeostasis and antiviral immunity. Proceedings of the National Academy of Sciences, USA, 108(37): 15312-17.
Newton R.H., Leverrier S., Srikanth S., Gwack Y., Cahalan M.D., Walsh C.M. 2011. Protein kinase D orchestrates the activation of DRAK2 in response to T cell receptor induced extracellular calcium uptake and mitochondrial reactive oxygen generation. J. Immunol. 186:940-950.
Walsh C.M., Edinger A.L. 2010. The complex interplay between autophagy, apoptosis and necrotic signals promotes T cell homeostasis. Immunological Reviews 236:95-109.
Walsh C.M., Bell B.D. 2010. T cell intrinsic roles of autophagy in promoting adaptive immunity. Current Opinion in Immunology 22(3) 321-325.
Hernandez J.B., Newton R.H., Walsh C.M. 2010. Life and death in the thymus—cell death signaling during T cell development. Current Opinion in Cell Biology 22:865-871.
Leverrier S., Salvesen G.S., Walsh C.M. 2011. Enzymatically active single chain caspase-8 maintains T cell survival during clonal expansion. Cell Death and Differ. 18:90-9.
Gatzka M., Newton R.H., Walsh C.M. 2009. Altered thymic selection and increased autoimmunity caused by ectopic expression of DRAK2 during T cell development. Journal of Immunology 183:285-297.
Bell B.D., Walsh C.M. 2009. Coordinate regulation of autophagy and apoptosis in T cells by death effectors: FADD or Foundation. Autophagy 5(2): 238-240.
Ramos S.J., Hernandez, J.B., Gatzka M., Walsh C.M. 2008. Enhanced T cell apoptosis within Drak2-deficient mice promotes resistance to autoimmunity. Journal of Immunology, 181:7606-7616.
Bell B.D., Leverrier S., Weist B.M., Newton R.H., Arechiga A.F., Morrissette N.S., Walsh C.M. 2008. FADD and caspase-8 are essential for controlling the outcome of autophagic signaling in proliferating T cells. Proceedings of the National Academy of Sciences, USA, 105(43): 16677-16682.
Gatzka M., Walsh, C.M. 2008. Negative Regulation of TCR Signaling in Immunological Tolerance: Taming Good and Evil. Current Immunology Reviews, 4(4): 190-198.
Al-Qahtani A., Xu Z., Zan H., Walsh C.M., Casali P. 2008. A role for DRAK2 in the germinal center reaction and the antibody response. Autoimmunity, 41:341-352.
Arechiga A.F., Bell B.D., Porter, M., Wu, Z., Kanno, Y., Ramos S.J., Ong S.T., Siegel R.M., Walsh C.M. 2007. A FADD/Caspase-8 signaling axis promotes S-phase entry and maintains S6 kinase activity. Journal of Immunology 179: 5291 - 5300.
Gatzka M., Walsh., C.M. 2007. Apoptotic signal transduction and T cell tolerance. Autoimmunity 40:442-452.
Friedrich M.L., Cui M., Hernandez J.B., Weist B.M., Andersen H.M., Zhang X., Huang L., Walsh C.M. 2007. Modulation of DRAK2 autophosphorylation by antigen receptor signaling in primary lymphocytes. Journal of Biological Chemistry 282: 4573-4584.
Ramos S.J.*, Hardison J.L.*, Stiles L.N., Lane T.E., Walsh C.M. 2007. Anti-viral effector T cell responses and trafficking are not dependent upon DRAK2 signaling following viral infection of the central nervous system. Autoimmunity 40(1):54-65.
Werner M.H., Wu C., Walsh, C.M. 2006. Perspective - Emerging roles for the death adaptor FADD in death receptor avidity and cell cycle regulation. Cell Cycle 5(20): 2332-38.
Choudhary S.K., Walker R.M., Powell D.M., Planelles V., Walsh C., Camerini D. 2006. CXCR4 Tropic Human Immunodeficiency Virus Type 1 Induces an Apoptotic Cascade in Immature Infected Thymocytes that Resembles Thymocyte Negative Selection. Virology 352:268-84.
Sandu C, Morisawa G, Wegorzewska I, Huang T, Arechiga AF, Hill JM, Kim T, Walsh CM, Werner MH. 2006. FADD self-association is required for stable interaction with an activated death receptor. Cell Death and Differentiation 13: 2052-2061.
Arechiga AF, Bell BD, Solomon JC, Chu IH, Dubois CL, Hall BE, George TC, Coder DM, Walsh CM. 2005. Cutting Edge - FADD is not required for antigen receptor mediated NF-kappaB activation. Journal of Immunology 175: 7800-7804.
Friedrich ML, Wen BG, Bain G, Kee B, Murre C, Hedrick SM, Walsh CM. 2005. DRAK2, a lymphoid-enriched DAP kinase, regulates the T cell receptor activation threshold during thymocyte selection. International Immunology, 17: 1379-1390.
McGargill MA, Wen BG, Walsh CM, Hedrick SM. 2004. A deficiency in Drak2 results in a T cell hypersensitivity and an unexpected resistance to autoimmunity. Immunity 21: 781-91.
Li C, Arechiga AF, Melo JV, Walsh CM, Ong ST. 2003. Bcr-Abl Kinase Modulates the Translation Regulators Ribosomal Protein S6 and 4E-BP1 in Chronic Myelogenous Leukemia Cells via mTOR. Cancer Research 63: 5716-22.
Walsh CM, Luhrs KA, Arechiga AF. 2003. The “fuzzy logic” of the death-inducing signaling complex in lymphocytes. Journal of Clinical Immunology 23:333-353.
Beisner D, Chu IH, Arechiga AF, Hedrick SM , Walsh CM. 2003. The requirements for FADD signaling in mature T cell activation and survival. Journal of Immunology.17: 247-56.
American Association of Immunologists
The American Society for Biochemistry and Molecular Biology
National Multiple Sclerosis Society
American Heart Association
Immunology and Pathogenesis
Cancer Research Institute
Institute for Immunology