This proposal aims at establishing the specific structural traits and functional properties of various T and B lymphocytes in the immune reactivity involved in pulmonary granuloma formation. Many human diseases, including tuberculosis, leprosy, sarcoidosis, berylliosis, leishmaniasis, and parasitic infections, display a complex inflammatory process known as granulomatosis. Most studies to date have focused on the macrophages which accumulate in granulomas, and little is known on the role of the lymphoid components of the immune system in the evolution of granulomatosis. Our project is now particularly challenging since recent advances in T cell immunology have revealed that in the lung, besides the well established """"""""classical"""""""" T cell clonotypes, newly described T cell subsets are present: such cells, which do not express the usual effector T cell markers CD4 and CD8, may bear the conventional alpha/beta T cell receptor or the intriguing, recently identified, gamma/delta T cell receptor. Interestingly, gamma/delta T cells have been found to accumulate in the skin granulomas of patients suffering from leprosy and leishmaniasis. Moreover, such cells can be induced to secrete factors responsible for macrophage aggregation and activation. In addition, pulmonary gamma/delta T cells can react to mycobacterial antigens and self-induced stress proteins. Our own contribution to this field as well as to the molecular genetics of pulmonary gamma/delta T cells will be exposed in the Preliminary Data section. We now propose to apply our knowledge of these pulmonary lymphocytes to a detailed investigation aiming at elucidating the role of various lymphocyte subsets in the initiation, development and establishment of pulmonary granulomas in murine experimental systems. To this end various agents (mycobacterial antigens, metals, non-specific micro-foreign bodies) will be used via different routes of administration to induce pulmonary granulomas, and the evolution of the pathological processes will be closely followed in time. The T cell subsets participating actively at any point in granuloma formation will be identified in situ, isolated in vitro, and characterized in structural and genetic terms. The molecular biology of these receptors will be explored, and the patters of clonotypes selection will be determined. Various tissue culture technologies, biochemical, and molecular biology analysis which are performed routinely in our laboratory, will be used to achieve these aims. Particular efforts will be dedicated to identifying specific cytokines produced by individual cell subsets in lung granulomas as well as in establishing the specific control of immunoglobulin switch (in resident B cells) in lung granulomas. The long term objective of our work is the understanding in depth of the immune mechanisms which are activated in the lung during granuloma formation, and to elucidate, at the molecular level, the genetic control of specific T and B cell functions in this process.
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