Analysis of immune system in Mycobacterium tuberculosis-infected lung and vaccine development.

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In this research, we analyzed kinetics of mycobacterial Ag-specific CD4^+ T cells response in the Mycobacterium tuberculosis-(Mtb)-infected lung of mice. To detect mycobacterial Ag-specific T cells, we used transgenic mice (P25-TCR Tg mice) expressing T cell receptor (TCR) from CD4^+ T cells specific for mycobacterial Ag85B. In the first series of experiments, we transferred the transgenic CD4^+ T cells into wild type mice, then intratracheally infected the mice with Mtb. Although the transferred transgenic T cells were specific to mycobacterial Ag, we failed to detect clear Th1 response of the transgenic T cells in the Mtb-infected lung and its draining lymph nodes. We hypothesized that transferred transgenic T cells were not detected in the lung because T cell response in the lung delays compared to other sites, and transferred T cells failed to proliferate during the analysis. This may be resulted in dilution of transferred T cells by newly emigrated T cells from thymus during the a … More ssay. To address the possibility, we next infected P25-TCR Tg mice themselves. Th1-type immune response of the transgenic CD4^+ T cells was not detected in the lung draining lymph nodes and the lung infiltrating cells until more than 2 weeks after Mtb lung infection. Ag85B-expressing attenuated bacteria, M.bovis BCG, also failed to induce Th1 response in the lung of P25-TCR Tg mice at early stage of infection. On the other hand, subcutaneous infection of BCG induced Th1 response in the draining inguinal and popliteal lymph nodes from day 3 after inoculation. This demonstrates that P25-TCR Tg mice can develop Th1 type immune response to Ag85B quickly outside the lung. All the results suggest that protective immune response against Mtb delays in the lung. This may support establishment of pulmonary tuberculosis especially when protective immune response is not induced in the lung immune system. Although the mechanism of the retardation of lung immune response is not yet clearly identified, further information on the mechanism may support development of new vaccine targeted to the lung to induce protective immunity against pulmonary tuberculosis. Less