CD4+ helper/inducer T-lymphocytes play a critical role in the immune response to M. tuberculosis. For more effective preventative measures to be designed, it is critical to gain insight into the human T-cell response to this pathogen. The availability of recombinant DNA-derived mycobacterial antigens and the identification of subsets of CD4+ T-cells defined by profiles of lymphokine secretion and function allow for new appraches to the study of the human CD4+ T-cell response to M. tuberculosis. The three specific objective are: 1) Characterize the heterogeneity of CD4+ T-lymphocytes from healthy subjects infected with M. tuberculosis: Peripheal blood T-cell and T-cell clones will be studied for their proliferative respones to crude mycobacterial antigens, their patterns of lymphokine secretion in particular IL-2, IL-4 and interferon-gamma, and the frequency of the phenotypic markers 2H4 and 4B4 which define subsets of human CD4+ T-cells. 2) Determine the antgenic specificity and functional capabilities of M. tuberculosis reactive CD4+ T-cell clones: T-cell clones from healthy tuberculin posens, to define epitopes on these antigens, to evaluate activation requirements of CD4+ T-cells and to determine their functional characteristics in terms of macrophage activation and helper function for B-cells. 3) Compare the distribution and function of CD4+ T-lymphocytes from healthy tuberculin positive persons and patients with tuberculosis: Peripheral blood T-cells defined by 2H4 and 4B4 sufface markers, the precursor frequency of M. tuberculosis- secretion, activation of marcrophages and ability to provide B-cell help. These studies will characterize the human CD4+ lymphocyte response to M. tuberculosis. An understanding of the human CD4+ T-cell response is necessary for any effortto design a more effective vaccine for M. tuberculosis, which is a major cause of morbidity and mortality worldwide. These studies are therefore, directly healthy-related.
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