We shall continue our investigation of the role of lymphokines in the activation of B cells. Interleukin 1 (IL-1) has traditionally been the focus of our lymphokine studies; it conditions B cells to differentiate into antibody-producing cells when intracellular cAMP levels are elevated. We propose that TRF (or interferon) is a factor which controls intracellular cAMP levels and thus B-cell differentiation. B-cell proliferation, through which antigen-reactive B cells increase their clone size, is controlled by interleukin-2 (IL-2). We propose further that IL-2 helps B cells sustain cell division after they receive proliferative stimulus from antigen; IL-2 curbs an intracellular (cAMP-mediated) mechanism which turns proliferation off. T cell- and macrophage-derived lymphokines are released as a consequence of MHC-restricted interaction between T cells and macrophages. The T cell recognizes in this interaction foreign antigen as well as MHC antigen on the macrophage surface. We propose that the T-cell receptor recognizes both antigens in unmodified form and that foreign antigen facilitates the interaction of the T-cell receptor with MHC antigen as a consequence of which effector function (e.g., release of IL-1 and IL-2) ensues. This process does not occur spontaneously, because T cells and macrophages mask receptor and MHC antigen with charged carbohydrates. Removal of these charged molecules from cell surfaces initiates polyclonal T-cell and macrophage-effector function. (HF)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA017673-11
Application #
3164773
Study Section
Immunobiology Study Section (IMB)
Project Start
1978-09-01
Project End
1987-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
11
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Sahdev, I; O'Reilly, R; Hoffman, M K (1989) Correlation between interleukin-1 production and engraftment of transplanted bone marrow stem cells in patients with lethal immunodeficiencies. Blood 73:1712-9
Hammerling, U; Toulon, M; Chun, M et al. (1988) Bidirectionality of mixed lymphocyte stimulation (Mls) response. Effects of Mlsb stimulator cells on Mlsa helper cells. J Immunol 140:2543-8
Hoffmann, M K (1988) The requirement for high intracellular cyclic adenosine monophosphate concentrations distinguishes two pathways of B cell activation induced with lymphokines and antibody to immunoglobulin. J Immunol 140:580-2
Hoffmann, M K; Chun, M; Dennig, D et al. (1988) Mls and the helper T-cell repertoire: II. Does the Mls gene product influence the formation of the T-cell repertoire? Studies with Mls tolerance. J Immunogenet 15:175-81
Mittler, R S; Greenfield, R S; Schacter, B Z et al. (1987) Antibodies to the common leukocyte antigen (T200) inhibit an early phase in the activation of resting human B cells. J Immunol 138:3159-66
Hoffmann, M K (1987) An alternate B cell activation mechanism mediated by macrophages through the release of cyclo-oxygenase pathway products and interleukin 1. Lymphokine Res 6:299-308
Chun, M; Hoffmann, M K (1987) Intracellular cAMP regulates the cytotoxicity of recombinant tumor necrosis factor for L cells in vitro. Lymphokine Res 6:161-7
Livingston, P O; Cunningham-Rundles, S; Marfleet, G et al. (1987) Inhibition of suppressor-cell activity by cyclophosphamide in patients with malignant melanoma. J Biol Response Mod 6:392-403
Trenkner, E; Hoffmann, M K (1986) Defective development of the thymus and immunological abnormalities in the neurological mouse mutation ""staggerer"". J Neurosci 6:1733-7
Hoffmann, M K; Chun, M; Hirst, J A (1986) Conditional requirement for accessory cells in the response of T cells to Con A. Lymphokine Res 5:1-9

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