CAPACITY OF MURINE T-CELLS TO RETAIN LONG-TERM RESPONSIVENESS TO MYCOBACTERIAL ANTIGENS IS CONTROLLED BY THE H-2-COMPLEX

It is firmly established that the allelic composition of the H-2 compl ex has a prominent impact on the course of tuberculosis (TB) infection in mice, including granuloma formation, mycobacterial spread in the l ungs, and the dynamics of mortality. Although intuitively obvious, the role of long-term specific T cell responses in the expression of corr esponding phenotypes is poorly understood. In this study we have compa red polyclonal lymph node cell response (cell yield, proliferation, su rface markers, IL-4/interferon-gamma (IFN-gamma) production) to Mycoba cterium tuberculosis H37Rv sonicate in repeated 10-day cycles of stimu lation/rest between H-2 congenic IE-negative mouse strains, categorize d on the basis of mortality following lethal challenge as TB-susceptib le (C57B1/6). TB-resistant (4R) and BCG non-protected (B10.M). The cap acity to retain specific responsiveness to repeated stimulation by myc obacterial antigens depended upon both the H-2 haplotype of the host a nd the immunizing dose of the antigen. 4R lymph node cells following e ither 50 mu g/mouse or 100 mu g/mouse immunization constantly responde d to sonicate, increased in numbers, and after the third stimulation/r est cycle developed into a stable CD3(+) CD4(+) cell Line. B6 cells fo llowing either 50 mu g/mouse or 100 mu g/mouse immunization, and B10.M cells following 100 mu g/mouse (but not 50 mu g/mouse) immunization l ost the capacity to incorporate methyl-H-3-thymidine during the second cycle, and died. Analogous results were obtained in the in vivo exper iments, when the dynamics of the response over 12 weeks following a si ngle immunization with the antigen was studied. In response to the ant igen, cells from all three mouse strains produced significant amounts of IL-2 and IFN-gamma, but not IL-4. indicating that they belong predo minantly to the Th1-like subset. Among noteworthy differences between the mouse strains was a clear deficiency of CD8(+) T cells in B6 cultu res, and an unusually high proportion of CD3(+)CD4(-)CD8(-) (double-ne gative) T cells in B10.M cultures following a high-dose immunization.