A comprehensive analysis of the role of IL1 on the antigen specific activation of class II-restricted cloned murine T lymphocytes will be done using two complementary T cell activation model systems. One system will utilize recombinat IL1 to enchance the activation of cloned, soluble antigen or alloantigen reactive T lympocytes stimulated in the presence of cloned B lymphoma accessory cells have been shown to activate T cell clones in antigen specific but IL1 independent fashion. The second module system will utilize combinations of recombinant IL1 and specific pharmacological modifiers of Ca++ (ionomycin) and protein kinase C (TPA, synthetic diacylglycerol) second messenger pathways to activate antigen and alloantigen reactive T cell clones. We have demonstrated that these soluble mediators effectively synergize with ionomycin in this system to elicit T cell activation responses. T cell clones which are either IL1 responsive or IL1 unresponsive in both assay systems have been identified and will be used as positive and negative experimental models. With these model systems we will quantitatively evaluate the effects of rIL1 and the parmacological modifiers on: A. The expression on the release of IL2 and of cell surface receptors that are directly involved in T cell activation, B. Activation of the phospholipase C-mediated hydrolysis of phosphoinositides, C. Identification of proteins which are phosphorylated as a result of the various initiators of T cell Activation, and D. Characterizartion by Northern blot and nuclear run off analyses of mRNA transcription which results from the various initiators of T cell activation. These analyses should significantly add to our understanding of the role of IL1 in regulating an antigen specific immune response. In addition, valuable information concerning the specific intracellular effects that may be related to cell transformation will be obtained using the tumor promoting phorbol esters (e.g. TPA).

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Immunobiology Study Section (IMB)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Sharp, B M; Shahabi, N A; Heagy, W et al. (1996) Dual signal transduction through delta opioid receptors in a transfected human T-cell line. Proc Natl Acad Sci U S A 93:8294-9
McKean, D J; Bell, M; Huntoon, C et al. (1995) IL-1 receptor and TCR signals synergize to activate NF-kappa B-mediated gene transcription. Int Immunol 7:9-20
McKean, D J; Huntoon, C; Bell, M (1994) Ligand-induced desensitization of interleukin 1 receptor-initiated intracellular signaling events in T helper lymphocytes. J Exp Med 180:1321-8
McKean, D J; Podzorski, R P; Bell, M P et al. (1993) Murine T helper cell-2 lymphocytes express type I and type II IL-1 receptors, but only the type I receptor mediates costimulatory activity. J Immunol 151:3500-10
Ruegemer, J J; Ho, S N; Augustine, J A et al. (1990) Regulatory effects of transforming growth factor-beta on IL-2- and IL-4-dependent T cell-cycle progression. J Immunol 144:1767-76
Pisani, R J; Leibson, P J; McKean, D J (1989) In vitro activation of lymphocytes from nonsmall cell cancer patients by interleukin 2 and anti-CD3 antibody. Clin Immunol Immunopathol 50:348-63
Pisani, R J; Krco, C J; Wold, L E et al. (1989) Lymphokine-activated killer (LAK) cell activity in tumor-infiltrating lymphocytes from non-small cell lung cancer. Am J Clin Pathol 92:435-46
Ho, S N; Abraham, R T; Nilson, A et al. (1987) Interleukin 1-mediated activation of interleukin 4 (IL 4)-producing T lymphocytes. Proliferation by IL 4-dependent and IL 4-independent mechanisms. J Immunol 139:1532-40
Abraham, R T; Ho, S N; Barna, T J et al. (1987) Transmembrane signaling during interleukin 1-dependent T cell activation. Interactions of signal 1- and signal 2-type mediators with the phosphoinositide-dependent signal transduction mechanism. J Biol Chem 262:2719-28