Evidence inconsistent with a negative influence of T helper 2 cells on protection afforded by a dominant T helper 1 response against Mycobacterium tuberculosis lung infection in mice.

The rational design of an antituberculosis vaccine capable of protecting susceptible humans will be based on a detailed knowledge of the type of immunity that provides most humans with the ability to resist the disease. Most of our recent knowledge about immunity to tuberculosis comes from studies of tuberculosis in mice that have been rendered incapable of generating one or more lymphocyte subpopulations by targeted gene deletion. According to these studies, immunity to Mycobacterium tuberculosis infection is mediated predominately by M. tuberculosis-specific CD4 and CD8 αβ T cells (5, 8, 13, 35). The responsible CD4 T cells are Th1 cells, as evidenced by the demonstration that protective immunity is not generated in mice subjected to targeted gene deletion and thereby rendered incapable of making interleukin-12 (IL-12) (7) or gamma interferon (IFN-γ) (6, 14). It is generally agreed that the function of IFN-γ secreted by Th1 cells is to activate the antimycobacterial functions of the macrophages in which M. tuberculosis bacilli reside at sites of infection. In order for macrophages to express immunity, however, they must generate the inducible isoform of nitric oxide synthase (NOS2) that catalyzes high-output generation of NO from l-arginine. Mice rendered incapable of synthesizing NOS2 are greatly deficient in an ability to express anti-M. tuberculosis immunity, as evidenced by progressive M. tuberculosis growth in major organs and early death (24, 38). However, Th1-mediated immunity, as expressed by activated macrophages, is not successful at resolving infection but functions, instead, to control M. tuberculosis growth and hold infection at a stationary level from about day 20 of infection on (for a discussion, see reference 27). This is of limited usefulness to the host, however, because stationary-level lung infection induces progressive lung pathology that is eventually lethal (10, 11). Presumably, therefore, in order for mice to successfully defend against tuberculosis, they would need to be capable of completely resolving lung infection or of reducing it to a level incapable of inducing pathology. It is generally assumed that this would require the generation of higher levels of Th1-mediated immunity. A possible reason for the inability of Th1-mediated immunity to resolve M. tuberculosis infections is that conditions arise during the course of infection that favor the production of M. tuberculosis-specific Th2 cells over Th1 cells (17, 34). This would be in keeping with the Th1/Th2 paradigm that has been invoked by some to explain the failure of Th1-mediated immunity to protect mice against infection with Leishmania major (23) in particular and against intracellular microbial infections in general (18, 22, 39). In keeping with this explanation are publications (17, 31) showing that an early Th1 response to M. tuberculosis infection in mice is joined by a Th2 response at about the time that infection enters a chronic phase. A similar Th1-to-Th2 response sequence has been shown to occur in mice infected with Mycobacterium bovis BCG (36) and Mycobacterium avium (1). The presence of T cells secreting Th2 cytokines in humans with active tuberculosis has likewise been taken as evidence that a Th2 response is responsible in part for progression of disease (2, 45). One way to test whether a Th2 response is responsible for the inadequacy of Th1-mediated immunity would be to determine whether mice rendered deficient in the ability to generate a Th2 response are capable of generating higher levels of Th1-mediated immunity to M. tuberculosis and of causing the infection to resolve. It is known (21, 42), in this regard, that the efficient generation of a Th2 response requires the synthesis and secretion of the Th2-polarizing cytokines IL-4 and IL-13, which, on binding to their respective receptors on T cells, activate the Stat6 pathway for transcriptional activation of Th2 cytokine genes. Therefore, if a Th2 response is responsible for the inability of Th1-mediated immunity to resolve M. tuberculosis infection, mice in which the genes encoding IL-4 plus IL-13 or Stat6 have been functionally deleted should generate a higher level of immunity and show more resistance to M. tuberculosis infection than wild-type (WT) mice. The same should apply to mice in which the gene for the IL-4 receptor alpha chain (IL-4Rα) has been deleted, since IL-4Rα is a common component of IL-4R and IL-13R. The purpose of this paper is to show that mice in which the aforementioned genes have been deleted are no more capable than WT mice at defending against M. tuberculosis infection.