Toxic environmental agents are capable of altering T-lymphocyte functions which could lead to immune dysfunctions resulting in increased incidence of infectious diseases, cancer, and/or autoimmune diseases. Since T-cells are important immune regulators, it is hypothesized that immunotoxicity could, in part, result from direct or indirect alteration of thiol moieties on constitutive or regulatory molecules within T-cells or on their surface membrane. Therefore, it is proposed to comparatively examine the effects of thiol-reactive chemicals and radiation (inducers of oxidative stress) on the biochemistry and functions of T-cells. The ability of thiols, thiol-blockers, oxidants and antioxidants, as well as irradiation, to alter the subcellular mechanisms necessary for the activation of T-cell growth, differentiation, and/or functions will assessed. The T-cell subpopulations have different characteristics, sensitivities, and reactivities. Any differences in their thiol chemistry, including glutathione content, will be explored and exploited to aid the evaluation of their biologic differences such as radiosensitivity, macrophage requirements, and production of factors (helper or suppressor). The biochemical analysis of the T-cell subsets will include the following: i) quantitation of surface thiols and intracellular GSH, ii) assessment of thiol-related modulation of amino acid transport, protein and DNA synthesis, iii) evaluation of quantitative and qualitative differences in thiol-containing membrane proteins, and iv) assay of thiol-related cellular phosphorylations. The homogeneous nature of cloned T-cells, T-cell hybridomas, and T-cell tumor lines will aid in the analysis of the thiol-related sensitivities and activities of T-cell subsets. Subcellular differences between the T-cell subsets, subsets of cloned T-cells, and T-cell tumor lines can be compared so that we may obtain a better understanding of the correlation between T-cell structure and function. Evaluation of some biochemical changes involved in the stimulation of the different types of T-cells will aid in the assessment of differences between non-proliferating and rapidly proliferating T-cells and the processes involved in modulating lymphocyte activation, differentiation, and growth. The mechanism(s) of toxic changes caused by thiol-reactive physical and chemical agents may be defined in these analyses.
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