CD8 T CELLS IN MICE WITH DIFFERENT GENETIC SUSCEPTIBILITY TO ANTI-TUBERCULOUS IMMUNE RESPONSE

Abstract

   In spite of decades of studying the role for CD8⁺ T-cells in response to tuberculosis (TB) infection, it remains only partly understood. Even less is known how the level of host genetic susceptibility to TB infection influences the involvement of these cells in immune response. Our lab established MHC-II-congenic mouse strains with different levels of genetic susceptibility to TB infection dependent exclusively upon quantitative and qualitative differences in organization of relevant CD4 T-cell populations and lacking major defects in immune systems. In the present work, we investigated how the in vivo lack of CD8⁺ T-cells affects related capacity to combat TB infection. To this end, we developed a novel double-congenic mouse strain В6.I-9.3-β₂M-/- that lacks CD8 T cells due to a knockout mutation in the gene encoding β₂-microglobulin and differs from the parental B6 strain by the MHC-II allele. We performed a comparative study of TB development and immune response using four mouse strains: the ancestor В6 and B6.I-9.3 pair vs. CD8-deficient В6-β2M-/- and В6.I-9.3-β2M-/- pair. CD8 T-cell deficiency did not alter lung mycobacterial multiplication during the first 4 weeks post TB challenge; however, at day 90 lung mycobacterial population increased to significantly higher levels in В6β2М-/- compared to B6 mice. Post-infection life span of both CD8 T-cell-deficient mouse strains was dramatically shorter than that of the wild type animals. En mass, negative effects of CD8 cell deficiency looked more pronounced on the MHC-II allele background, which in the presence of CD8 cells is associated with better protection against infection. In addition, the lack of CD8⁺ cells resulted in significantly decreased size of TNF-positive CD4⁺ T-cell populations in mice from both β2M-/- strains at week 4 post-challenge.  This is consistent with a previously non-described helper function of CD8 cells for the TNF synthesis by CD4 cells. We discuss the results obtained within the context of dynamical interactions between T-cell populations during chronic TB infection.