The long term objective of this research proposal is to gin new insights into the detailed molecular and cellular events which are triggered by recognition of foreign antigens and which generate the appropriate immune responses. In particular, the studies will be aimed at understanding the molecular and cellular mechanisms of specific cell:cell interactions, and how such interactions cause the activation and differentiation of Beta cells by T-helper (Th) cells, as well as T cell selection in the thymus. These studies will be conducted primarily at the single cell level using double and triple immunofluorescence microscopy. Such cell biological techniques already demonstrated the in vitro formation of specific stable Th:Beta-cell conjugates, and have identified several important early intracellular and membrane events triggered by such T:B interactions. The results of these studies will increase our knowledge of the mechanisms by which cells of the immune system can protect against invading microorganisms, viral infections, and some malignancies.
The specific aims of the proposed research are: 1. To study intracellular and membrane rearrangements induced by the interactions of cloned Th (Th1, Th2) cells with resting Beta cells which will be either Ag/MHC specific, non-specific or bystander (non-specific in the presence of specific) Beta cells. 2. To study the spatial and temporal induction of lymphokine (e.g. IL2, IL4) secretion in specific and mixed (bystander) T:B conjugates. 3. To study the activation and differentiation of resting Beta cells in T;Beta conjugates, including complex conjugates in which several Beta cells are simultaneously bound to one T cell. 4. To continue to study the signalling mechanisms that trigger the intracellular and membrane rearrangements, which were identified before in specific T: Beta and CTL:TC conjugates. 5. To study the signalling mechanisms in defined populations of immature T cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI023764-07
Application #
3136146
Study Section
Immunobiology Study Section (IMB)
Project Start
1986-09-01
Project End
1994-07-31
Budget Start
1992-09-01
Budget End
1993-07-31
Support Year
7
Fiscal Year
1992
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206
Schaefer, Brian C; Kappler, John W; Kupfer, Abraham et al. (2004) Complex and dynamic redistribution of NF-kappaB signaling intermediates in response to T cell receptor stimulation. Proc Natl Acad Sci U S A 101:1004-9
Miranda, Luis R; Schaefer, Brian C; Kupfer, Abraham et al. (2002) Cell surface expression of the HIV-1 envelope glycoproteins is directed from intracellular CTLA-4-containing regulated secretory granules. Proc Natl Acad Sci U S A 99:8031-6
Marschner, S; Freiberg, B A; Kupfer, A et al. (1999) Ligation of the CD4 receptor induces activation-independent down-regulation of L-selectin. Proc Natl Acad Sci U S A 96:9763-8
Sperling, A I; Sedy, J R; Manjunath, N et al. (1998) TCR signaling induces selective exclusion of CD43 from the T cell-antigen-presenting cell contact site. J Immunol 161:6459-62
Nagasawa, M; Melamed, I; Kupfer, A et al. (1997) Rapid nuclear translocation and increased activity of cyclin-dependent kinase 6 after T cell activation. J Immunol 158:5146-54
Sinensky, M; Fantle, K; Trujillo, M et al. (1994) The processing pathway of prelamin A. J Cell Sci 107 ( Pt 1):61-7
Kupfer, H; Monks, C R; Kupfer, A (1994) Small splenic B cells that bind to antigen-specific T helper (Th) cells and face the site of cytokine production in the Th cells selectively proliferate: immunofluorescence microscopic studies of Th-B antigen-presenting cell interactions. J Exp Med 179:1507-15
Podack, E R; Kupfer, A (1991) T-cell effector functions: mechanisms for delivery of cytotoxicity and help. Annu Rev Cell Biol 7:479-504
Kupfer, A; Mosmann, T R; Kupfer, H (1991) Polarized expression of cytokines in cell conjugates of helper T cells and splenic B cells. Proc Natl Acad Sci U S A 88:775-9
Kupfer, A; Burn, P; Singer, S J (1990) The PMA-induced specific association of LFA-1 and talin in intact cloned T helper cells. J Mol Cell Immunol 4:317-25

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