Stephen M. Hedrick Professor of Biology, UCSD e-mail: shedrick@ucsd.edu lab homepage publications (PubMed)

T cell activation, growth, and cell death. The induction of an adaptive immune response to infection starts with the activation of quiescent, antigen-specific T lymphocytes resulting in blast transformation and a dramatic expansion of the population. This process is self-limiting, and the expanded T cell population undergoes an equally dramatic contraction until there is but a pale memory of the original response. One of the mechanisms regulating T cells involves Death Receptors and the cascade of downstream events that can result in apoptosis. Enigmatically, the most important aspect of this pathway in the lymphocyte response to infectious agents is not death, but survival—T and B cells require the two proximal mediators of Death Receptor signaling, FADD and Caspase-8, in order to survive progression through the cell cycle. We have created mice with selective deficiencies in FADD and Caspase-8, and we have used these mice to dissect the role of Caspase-8 in innate and adaptive immunity¹⁰. Although fundamental to the regulation of lymphocyte homeostasis, the operative cellular mechanisms are completely uncharacterized.

Fate decisions in early T cell differentiation. T cell development selects for a population of quiescent mature cells able to interrogate major histocompatibility molecules expressed throughout the body. Individual cells in the population retain the potential to become overtly activated in the presence of pathogenic agents: viruses and microbial parasites. We are interested in the logic underlying the fate specification and selection of developing T cells, and we have concentrated on the MAP Kinase pathway as an arbiter of differentiation and survival. Toward this end we have produced mice deficient for Erk1,2 in T cells, and we have used these mice to dissect the role of this central pathway in several aspects of immune physiology¹¹. Present studies are focused the role of the MAP Kinase pathway in cell division and survival, and in the way it alters the program of gene transcription.

Intelligent design (of vaccines). The use of vaccines is arguably one of the most important advances in the history of medical science. Nonetheless, many diseases are still resistant to known strategies for vaccination. A new effort for our lab is to develop the means to deliver antigens in a way that promotes different types of immune responses tailored to individual pathogens. Single-chain antibodies directed against activating receptors on dendritic cell subsets are being designed and tested for efficacy in protective immunity.

1. McGargill, M., Wen, B. G., Walsh, C. M., and Hedrick, S. M. (2004). A deficiency in Drak2 results in a T cell hypersensitivity, and an unexpected resistance to autoimmunity. Immunity, 21:781-791.

2. Soloff, R. S., Katayama, C., Lin, M. Y., Feramisco, J. and Hedrick, S. M. (2004) Targeted deletion of PKC lambda reveals a distribution of functions between the two atypical PKC isoforms. J. Immunol. 173:3250-3260.

3. Hedrick, S. M. The acquired immune system: a view from beneath. (2004) Immunity, 21:607-615.

4. Sato, K, Imai, Y., Higashi, N., Kumamoto, Y., Onami, T. M., Hedrick, S. M. and Irimura, T. (2005). Lack of antigen-specific tissue remodeling in mice deficient in the macrophage galactose-type calcium-type lectin 1/CD301a. Blood 106:207-215.

5. Lin, M. Y., Zal, T., Ch’en, I. L., Gascoigne, N. R. J., and Hedrick, S. M. (2005). A Pivotal Role for the Multifunctional Calcium/Calmodulin-dependent Protein Kinase II in T Cells: from Activation to Unresponsiveness. J. Immunol. 174:5583-92.

6. Catlett, I., and Hedrick, S. M. Suppressor of Cytokine Signaling 1 is required for differentiation of CD4 T Cells (2005). Nature Immunology, 6:715-21.

7. McGargill, M.A., Sharp, L.L., Bui, J.D., Hedrick, S.M., Calbo, S. Active Ca2+/Calmodulin-Dependent Protein Kinase II<lambda>B Impairs Positive Selection of T Cells by Modulating TCR Signaling (2005). J. Immunol. 175:656-664.

8. Goldrath A. W., and Hedrick, S. M. Central Tolerance Matters. (2005) Immunity 23:113-114.

9. Hedrick SM, Cohen DI, Nielsen EA, Davis MM. Pillars article: isolation of cDNA clones encoding T cell-specific membrane-associated proteins. [Nature, 1984, 308: 149-153] J Immunol. 2005 Sep 1;175(5):2771-5.

10. Beisner D. R., Ch'en I. L., Kolla R.V., Hoffmann A., and Hedrick S. M. (2005). Cutting Edge: Innate Immunity Conferred by B Cells Is Regulated by Caspase-8 J. Immunol. 175: 3450-3455.

11. Fischer, A., Katayama, C. D., Pages, G., Pougyssegur, J., and Hedrick, S. M. The role of Erk1,2 in multiple stages of T cell development (2005). Submitted.