PERFORIN, A CYTOTOXIC MOLECULE WHICH MEDIATES CELL NECROSIS, IS NOT REQUIRED FOR THE EARLY CONTROL OF MYCOBACTERIAL INFECTION IN MICE

Host defense against mycobacterial infection requires the participatio n of monocytes and T cells, Both CD4(+) and CD8(+) T cells have been s hown to be important in resistance to mycobacterial infection in vivo, The main contribution of CD4(+) T cells to the protective antitubercu losis response involves the production of Th1-type cytokines, includin g interleukin-a (IL-2) and gamma interferon (IFN-gamma), CD8(+) T cell s have been considered to be responsible primarily for cytotoxicity me diated by toxic molecules, including perforin, CD8(+) T cells may also elaborate Th1-type cytokines, such as IFN-gamma, in response to the i nfection, To elucidate the contribution of perforin-mediated target ce ll death to the control of mycobacterial infection in vivo, mice with a disruption in the perforin gene (P--/-) were infected with Mycobacte rium bovis BCG or M, tuberculosis Erdman for 5 and 13 weeks, respectiv ely, At 1, 3, 5, and 13 weeks postinfection, the number of viable myco bacteria in the lungs, spleens, and livers of mice were determined by CFU assay, The infected tissues were examined histologically, and cyto kine mRNA levels in the spleens of these mice were determined, Similar studies were carried out in Fas receptor-defective (CBA/lpr(cg)) mice to evaluate the contribution of this alternative cytotoxic pathway to the control of mycobacterial infection, The absence of either perfori n gene function or Fas receptor gene function did not modify the cours e of experimental mycobacterial infection in these mice, In addition, both P--/- and Fas receptor-defective mice appeared to have a compensa tory activation of cytokine genes, even in the absence of the experime ntal infection, P--/- mice had a mean 3.4- to 5-fold increase in mRNA levels for IL-10, IL-12p35, IL-6, and IFN-gamma, Similarly, Fas recept or-defective mice had a mean 3- to 3.6-fold increase in mRNA levels fo r IFN-gamma, IL-12p35, and IL-10, Our results indicate that both perfo rin-mediated cytotoxicity and Fas-mediated cytotoxicity do not appear to be necessary for the early control of mycobacterial infection in vi vo.