Enhancement of the long term efficacy of BCG vaccine against experimental tuberculosis in mice through rapamycin induced modulation of CD4 and CD8 T cell functions (166.17)

Abstract

Abstract BCG vaccine protects children but does not induce long-term immunity against tuberculosis. Rapamycin has been found to directly act on MTOR of T cells and extend the longevity of CD8 T cell response to viral infection in mice. We hypothesized that rapamycin co-administration during BCG vaccination may alter the quality of CD8 function to enable long-term immunity. Methods: C57Bl/6 mice were given one dose of BCG vaccine (1 million per mouse; s.c.) or BCG with doses of rapamycin (75 microgram/mg given daily for 30 days) followed by aerosol infection with virulent Mycobacterium tuberculosis (Mtb). At 4 and 8 weeks, antigen specific CD8 T cells, memory specific markers and tetramers specific for Mtb antigens-ESAT6 and TB10.4 were analysed using flow cytometry. Log10 decline of Mtb counts in lungs was determined to correlate T cell phenotype with protection after vaccination. Results: Rapamycin coadministration with BCG enhanced the expansion of antigen-specific CD8 T cells in mice that correlated with a decline in the counts of Mtb in lungs and spleens of mice. Rapamycin increased both CD8 and CD4 T cells in the lungs and spleens and enhanced central memory (Tcm) CD8 T cells in lymphoid organs. Tcm levels, in turn, correlated with an increase in expression of Eomes transcription factor by CD8 T cells. Since Eomes is a determinant of Tcm lineage, we suggest that the long-term efficacy of BCG vaccine can be enhanced through modulation of MTOR dependent pathways of T cells.