Capacity of murine T cells to retain long-term responsiveness to mycobacterial antigens is controlled by the H-2 complex

Abstract

SUMMARY It is firmly established that the allelic composition of the H-2 complex has a prominent impact on the course of tuberculosis (TB) infection in mice, including granuloma formation, mycobacterial spread in the lungs, and the dynamics of mortality. Although intuitively obvious, the role of long-term specific T cell responses in the expression of corresponding phenotypes is poorly understood. In this study we have compared polyclonal lymph node cell response (cell yield, proliferation, surface markers, IL-4/interferon-gamma (IFN-γ) production) to Mycobacterium tuberculosis H37Rv sonicate in repeated 10-day cycles of stimulation/rest between H-2 congenic IE-negative mouse strains, categorized on the basis of mortality following lethal challenge as TB-susceptible (C57Bl/6), TB-resistant (4R) and BCG non-protected (B10.M). The capacity to retain specific responsiveness to repeated stimulation by mycobacterial antigens depended upon both the H-2 haplotype of the host and the immunizing dose of the antigen. 4R lymph node cells following either 50 μg/mouse or 100 μg/mouse immunization constantly responded to sonicate, increased in numbers, and after the third stimulation/rest cycle developed into a stable CD3+ CD4+ cell line. B6 cells following either 50 μg/mouse or 100 μg/mouse immunization, and B10.M cells following 100 μg/mouse (but not 50 μg/mouse) immunization, lost the capacity to incorporate methyl-3H-thymidine during the second cycle, and died. Analogous results were obtained in the in vivo experiments, when the dynamics of the response over 12 weeks following a single immunization with the antigen was studied. In response to the antigen, cells from all three mouse strains produced significant amounts of IL-2 and IFN-γ, but not IL-4, indicating that they belong predominantly to the Th1-like subset. Among noteworthy differences between the mouse strains was a clear deficiency of CD8+ T cells in B6 cultures, and an unusually high proportion of CD3+ CD4− CD8− (double-negative) T cells in B10.M cultures following a high-dose immunization.