CHEMOTACTIC ACTIVITY OF MYCOBACTERIAL LIPOARABINOMANNANS FOR HUMAN BLOOD T-LYMPHOCYTES IN-VITRO

A crucial early event in tuberculosis is the ingestion of Mycobaterium tuberculosis (Mtb) by alveolar macrophages, Chemotactic factors relea sed by infected macrophages are likely to initiate a granulomatous res ponse, a key feature of host resistance to tuberculosis. To date, the role of mycobacterial products in regulating the granulomatous respons e has not been clearly defined. Here we report that the mycobacterial cell wall glycophospholipid lipoarabinomannan (LAM) could specifically induce human peripheral blood T cell chemotaxis in vitro. Both termin ally mannosylated LAM isolated from Mtb and LAM lacking the terminal m annosyl units isolated from an avirulent mycobacterium could induce T cell migration in the absence of serum. in contrast, terminally mannos ylated LAM isolated from Mycobacterium bovis BCC failed to induce T ce ll chemotaxis. These observations represent the first report that LAM is capable of directly inducing biologic responses in human T cells. F low cytometry analysis revealed that CD4(+), CD8(+), and CD45RO(+) lym phocytes were present in the migrating cell populations at ratios simi lar to those found in nonmigrating cells. The chemotactic: response wa s found to require new protein synthesis, and could be blocked by inhi bitors of protein tyrosine kinases at concentrations that did not affe ct random migration. Acyl groups at the reducing terminus of LAM appea r to be required for the chemotactic activity of this mycobacterial gl ycolipid. Lastly, culture supernatants from human alveolar macrophages infected in vitro with a virulent strain of Mtb could induce T cell m igration. Much of the migratory activity present in these supernatants could be blocked using a mAb against LAM, suggesting that LAM is one of the chemotactic factors released by Mtb-infected alveolar macrophag es.