Evidence Inconsistent with a Negative Influence of T Helper 2 Cells on Protection Afforded by a Dominant T Helper 1 Response againstMycobacterium tuberculosisLung Infection in Mice

Abstract

Mice incapable of generating an efficient Th2 response because of functional deletion of the genes for signal transducer and activation of transcription 6 (Stat6), interleukin-4 receptor alpha chain (IL-4R␣), or IL-4 plus IL-13 (IL-4/IL-13) were no more resistant than wild-type (WT) mice to airborne infection with virulent Mycobacterium tuberculosis. WT mice were able to control infection and hold it at a stationary level following 20 days of log linear M. tuberculosis growth. Likewise, infection was kept under control and was held at the same stationary level in IL-4/IL-13 ؊/؊ mice but progressed to a slightly higher level in Stat6 ؊/؊ and IL-4R␣ ؊/؊ mice. The onset of stationary-level infection in WT mice was associated with the expression of Th1-mediated immunity, as evidenced by an approximately 100-to 1,000-fold increase in the lungs in the synthesis of mRNA for IL-12, gamma interferon (IFN-␥), and inducible nitric oxide synthase (NOS2) that was sustained for at least 100 days. IL-12 is essential for the induction of Th1 immunity, IFN-␥ is a key Th1 cytokine involved in mediation of immunity, and NOS2 is an inducible enzyme of macrophages and is needed by these cells to express immunity. In response to infection, the lungs of Stat6 ؊/؊ mice showed increases in synthesis of mRNA for IL-12, IFN-␥, and NOS2 similar to that seen in WT mice. In IL-4/IL-13 ؊/؊ mice, however, synthesis of mRNA for IFN-␥ and NOS2 reached higher levels than in WT mice. These results argue against the notion that a Th2 response is partly or wholly responsible for the inability of Th1-mediated immunity to resolve infection with a virulent strain of M. tuberculosis.

Increased Susceptibility of Mice Lacking T-bet to Infection withMycobacterium tuberculosisCorrelates with Increased IL-10 and Decreased IFN-γ Production

“…In some studies, IL-4-producing cells were detected at a late stage of tuberculosis (32). However, the majority of studies failed to associate susceptibility to tuberculosis with the presence of mycobacteria-specific Th2 cells (33,34). Instead, both live and killed mycobacteria had a remarkable propensity to bias activation of CD4 ϩ T cells toward a Th1 phenotype (35,36), perhaps via stimulation of IL-12 production by APCs.…”

Do successful tuberculosis vaccines need to be immunoregulatory rather than merely Th1-boosting?

“…The latter is interesting because there is a view that Th2 cytokines are needed for human pulmonary fibrosis, which is striking in TB, whereas IFN-γ downregulates fibrosis [9]. These effects will not be apparent in mouse strains where IL-4 is not induced during progressive disease, and most are probably not mediated via STAT-6 [10]. The "non-Th2" effects of IL-4 are signalled via IRS-1 and IRS-2.…”

Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

“…IL-4 has been suggested to be required for IL-10-producing T cells in vivo [17], and it remains to be elucidated whether IL-4 participates in the generation of regulatory T cells that suppress both Th1 and Th2 responses by secreting IL-10 and TGF-b [18]. Investigations aiming at elucidating the role of IL-4 in the murine model of tuberculosis have demonstrated that a lack of IL-4 signaling does not impair control of M. tuberculosis infection when IL-4 -/-alone [19], or IL-4 -/-/IL-13 -/-and IL-4Ra -/-mice on a C57BL/6 background were used [20]. In Balb/c mice deficient in STAT6, a transcription factor key to the generation of a functional Th2 response in the IL-4 signaling pathway, a slightly reduced bacterial load was observed only on day 120 post infection (p.i.)…”

“…In Balb/c mice deficient in STAT6, a transcription factor key to the generation of a functional Th2 response in the IL-4 signaling pathway, a slightly reduced bacterial load was observed only on day 120 post infection (p.i.) [20]. Reduced bacterial growth in the lungs of IL-4 -/-mice on the Balb/c background, altered histopathology, and delayed-type hypersensitivity responses indicate a suppressive effect of IL-4 on the Th1 response [21].…”