Interleukin-7 or interleukin-15 enhances survival of Mycobacterium tuberculosis-infected mice - PubMed (original) (raw)

Interleukin-7 or interleukin-15 enhances survival of Mycobacterium tuberculosis-infected mice

M J Maeurer et al. Infect Immun. 2000 May.

Abstract

Both antigen-presenting cells and immune effector cells are required to effectively eradicate or contain Mycobacterium tuberculosis-infected cells. A variety of cytokines are involved to ensure productive "cross talk" between macrophages and T lymphocytes. For instance, infection of macrophages with mycobacteria leads to effective interleukin-7 (IL-7) and IL-15 secretion, and both cytokines are able to maintain strong cellular immune responses of alpha/beta and gamma/delta T cells. Here we show that either cytokine is able to enhance survival of M. tuberculosis-infected BALB/c mice significantly compared to application of IL-2, IL-4, or phosphate-buffered saline (as a control). Enhanced survival could be achieved only when IL-7 or IL-15 was delivered as a treatment (i.e., 3 weeks postinfection), not when it was administered at the time of infection. Increased survival of M. tuberculosis-infected animals was observed following passive transfer of spleen cells harvested from M. tuberculosis-infected, IL-7- or IL-15-treated animals, but not after transfer of spleen cells obtained from mice which received either cytokine alone. Histological examination revealed that IL-7 and IL-15 failed to significantly impact on the number and composition of granulomas formed or the bacterial load. Our data indicated that administration of IL-7 or IL-15 to M. tuberculosis-treated animals resulted in a qualitatively different cellular immune response in spleen cells as reflected by increased tumor necrosis factor alpha and decreased gamma interferon secretion in response to M. tuberculosis-infected antigen-presenting cells.

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Figures

FIG. 1

FIG. 1

Treatment schedule. (A) Mice (n = 15/group) were i.v. infected with viable bacilli. After 3 weeks, they were treated i.p. for 7 consecutive days with three 100-ng doses of IL-2, IL-4, IL-7, or IL-15 or with PBS as a control. Alternatively, mice were infected and treated concomitantly for 7 days with cytokines. The bold arrows indicate infection with M. tuberculosis. (B) Animals were either injected with PBS or infected with M. tuberculosis (M.tub.). Each group (infected or noninfected [nil]) was treated i.p. for 7 days with either IL-7 or IL-15 (three 100-ng doses/day). After 7 days, spleen cells were harvested and tested for cytokine mRNA expression, cytotoxicity, and cytokine release. Spleen cells (3 × 107) or serum (0.3 ml) from individual animals were transferred by tail vein injection to individual animals which had been preinfected 3 weeks earlier with M. tuberculosis.

FIG. 2

FIG. 2

Effects of IL-2, IL-4, IL-7, IL-15, and PBS on survival of _M. tuberculosis_-infected BALB/c mice. Mice were treated either at the time of infection (left panel) or 3 weeks after infection with viable bacilli (right panel). Data are from one representative experiment (n = 15 mice/group) which was performed two times. Note that IL-7 or IL-15 enhanced survival if provided as a treatment (right panel). The arrows indicate completion of the 7-day cytokine treatment (left panel, days 1 to 7; right panel, days 21 to 27). See Table 1 for associated statistical analysis data.

FIG. 3

FIG. 3

Lack of a significant effect of IL-2, IL-4, IL-7, IL-15, or PBS on granuloma formation or liver pathology in animals killed at day 8 after infection and concomitant cytokine treatment. Formalin-fixed organs were stained with HE. Magnifications: NIL (PBS), ×680; IL-2, ×620, IL-4, ×516; IL-7, ×360; IL-15, ×564.

FIG. 4

FIG. 4

M. tuberculosis CFU in organs of infected BALB/c mice. Mice either were not infected (Nil) or infected with M. tuberculosis and after 3 weeks were treated with cytokines for 7 days as indicated in Materials and Methods. Organs were retrieved and CFU were determined. There were 5 mice per group. Experiments were performed twice. See Table 2 for associated statistical analysis of data from one experiment.

FIG. 5

FIG. 5

Cytokine gene expression in spleens. Mice were either noninfected (−) or infected with M. tuberculosis (+) and treated with IL-7 or IL-15. Five representative samples from individual animals are shown for each group. RNA was extracted, reverse transcribed into cDNA, and analyzed for cytokine expression by RT-PCR. Amplification of β-actin served as a positive control. Groups: A, M. tuberculosis negative, no treatment (NIL); B, M. tuberculosis positive, no treatment; C, M. tuberculosis negative, IL-7 treatment alone; D, M. tuberculosis infection plus IL-7 application; E, M. tuberculosis negative, IL-15 treatment alone; F, M. tuberculosis infection plus IL-15 treatment. No significant differences in cytokine expression could be observed within different treatment groups. In general, M. tuberculosis infection leads to decreased IL-2 and IL-4 and increased IL-10 mRNA expression.

FIG. 6

FIG. 6

Cytokines released in response to M. tuberculosis (M.tub)-infected macrophages. Peritoneal macrophages were harvested and infected with viable M. tuberculosis bacilli and served as antigen-presenting cells. Spleen cells were obtained either from noninfected animals, or from _M. tuberculosis_-infected mice which received either PBS, IL-7, or IL-15. Spleen cells from animals which received either IL-7 or IL-15 (without M. tuberculosis infection) served as controls. Note that antigen-presenting cells alone, i.e., without responder cells, secreted up to 310 pg of IL-10/ml (horizontal bar). However, IL-10 secretion as a response to _M. tuberculosis_-positive antigen-presenting cells was observed in spleen cells harvested from animals which had been infected with M. tuberculosis, irrespective of cytokine application. IL-7 and IL-15 treatment of _M. tuberculosis_-infected animals enhanced TNF-α secretion in spleen cells. Spleen cells from _M. tuberculosis_-infected animals secreted up to 83 pg of TNF-α/ml. In contrast, spleen cells obtained from IL-7- or IL-15-treated, _M. tuberculosis_-infected animals secreted up to 200 or 180 pg TNF-α/ml, respectively. In contrast, IL-7 or IL-15 treatment appears to decrease IFN-γ secretion as a response to _M. tuberculosis_-infected stimulator cells. Spleen cells from IL-7-treated infected mice secreted up to 110 pg and those from IL-15-treated animals secreted 80 pg of IFN-γ/ml in response to _M. tuberculosis_-infected macrophages, whereas spleen cells from _M. tuberculosis_-infected animals secreted up to 200 pg of IFN-γ/ml. No IL-4 secretion could be observed (data not shown). Data for each cytokine represent mean values for five individual animals as determined by ELISA. Error bars indicate standard deviations. P values of <0.01 are indicated with stars. Levels of cytokine secretion by spleen cells obtained from different treatment groups were compared to that by cells obtained from PBS (diluent)-injected mice. Exact P values (Wilcoxon two-sample test) are given in Table 4.

FIG. 7

FIG. 7

Passive transfer of spleen cells from M. tuberculosis (M.tub.)-infected animals treated with IL-7 or IL-15 enhances survival of animals which had been preinfected with M. tuberculosis. Animals were infected with viable bacilli and treated for 7 consecutive days with either IL-7, IL-15, or PBS. As a control, noninfected animals were treated with IL-7, IL-15, or PBS (see Fig. 1B). Spleen cells were harvested, and 3 × 107 cells from an individual animal were passively transferred via tail vein injection into an animal which had been preinfected (3 weeks earlier) with M. tuberculosis. As a control, serum from these individual treatment groups was passively transferred in _M. tuberculosis_-preinfected mice. Exclusively spleen cells harvested from animals which had been infected and treated with IL-7 or IL-15 could confer enhanced survival in preinfected mice (n = 15 mice/group). The arrows mark the points of passive transfer of serum or cells, respectively. See Table 5 for associated statistical analysis.

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