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The relative importance of T cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice.

Mogues T, Goodrich ME, Ryan L, LaCourse R, North RJ - J. Exp. Med. (2001)

Bottom Line: This was associated with the development of a macrophage-dominated alveolitis at sites of infection, with increased synthesis of IFN-gamma and NOS2 mRNA, and with an median survival time (MST) of 258.5 d.In the absence of CD4-mediated immunity (class II(-/-) mice), progressive bacterial growth continued in the lungs and in other organs beyond day 20, resulting in an MST of 77 d.By contrast, in the absence of CD8 T cell-mediated immunity, lung infection was controlled at a 1 log higher stationary level that induced a similar histopathologic response to that of WT mice, and resulted in an MST of 232 d.

View Article: PubMed Central - PubMed

Affiliation: The Trudeau Institute, Saranac Lake, New York 12983, USA.

ABSTRACT
Wild-type (WT) and targeted-mutant mice incapable of making alphabeta T cells, gammadelta T cells, class I major histocompatibility complex (MHC), class II MHC, interferon (IFN)-gamma, or inducible nitric oxide synthase (NOS2), were infected with Mycobacterium tuberculosis (Mtb) by aerosol, and monitored over time for their ability to (a) control infection, (b) develop histopathology at sites of infection, and (c) survive. WT mice acquired the ability to control and to hold infection at a stationary level from day 20 on. This was associated with the development of a macrophage-dominated alveolitis at sites of infection, with increased synthesis of IFN-gamma and NOS2 mRNA, and with an median survival time (MST) of 258.5 d. In the absence of alphabeta T cells, Mtb grew progressively and rapidly to induce a necrotic, neutrophil-dominated lung pathology that killed mice with an MST of 48 d. In the absence of CD4-mediated immunity (class II(-/-) mice), progressive bacterial growth continued in the lungs and in other organs beyond day 20, resulting in an MST of 77 d. By contrast, in the absence of CD8 T cell-mediated immunity, lung infection was controlled at a 1 log higher stationary level that induced a similar histopathologic response to that of WT mice, and resulted in an MST of 232 d.

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Low power (×25) and high power (×550) micrographs of lung sections of a WT (a and b), class I−/− (c and d), class II−/− (e and f), and TCR-α/β−/− mouse (g and h) stained for NOS2 by immunocytochemistry. At low power, the immunocytochemical reaction product is seen to be located in cells in the lightly stained macrophage areas of the lesions of WT and class I−/− mice. In class II−/− and TCR-α/β−/− mice, the reaction product is scattered in smaller quantity in cells throughout the lesions. At high power, the reaction product is seen confined to macrophages in lesions of WT and class I−/− mice, with some of the macrophages containing acid-fast bacilli. The NOS2-positive macrophages of the class I−/− mouse contain more acid-fast bacilli than NOS2-positive macrophages in WT lesion. In the lesion of the class II−/− mouse, NOS2-positive macrophages are heavily infected with Mtb, although some heavily infected macrophages have little or no reaction product. In the lesion of the TCR-α/β−/− mouse, most of the NOS2 reaction product appears to be concentrated in scattered mononuclear cells.
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Figure 9: Low power (×25) and high power (×550) micrographs of lung sections of a WT (a and b), class I−/− (c and d), class II−/− (e and f), and TCR-α/β−/− mouse (g and h) stained for NOS2 by immunocytochemistry. At low power, the immunocytochemical reaction product is seen to be located in cells in the lightly stained macrophage areas of the lesions of WT and class I−/− mice. In class II−/− and TCR-α/β−/− mice, the reaction product is scattered in smaller quantity in cells throughout the lesions. At high power, the reaction product is seen confined to macrophages in lesions of WT and class I−/− mice, with some of the macrophages containing acid-fast bacilli. The NOS2-positive macrophages of the class I−/− mouse contain more acid-fast bacilli than NOS2-positive macrophages in WT lesion. In the lesion of the class II−/− mouse, NOS2-positive macrophages are heavily infected with Mtb, although some heavily infected macrophages have little or no reaction product. In the lesion of the TCR-α/β−/− mouse, most of the NOS2 reaction product appears to be concentrated in scattered mononuclear cells.

Mentions: Histology was performed on lungs harvested on day 50 and day 80 of infection when infection in WT mice was being held in stationary phase by acquired immunity. However, only day 50 histology is shown, because certain mutant mice were dead by day 80. In mice that survived, day 80 histology was essentially the same as that seen at day 50, except that the lesions were somewhat larger. Low power microscopy of day 50 lung sections (Fig. 8) serve to show the size of individual lesions and the extent to which infection-induced pathology occupied the lungs. For example, it can be seen in Fig. 8 that infection-induced pathology was confined to discrete sites that were similar in appearance, number, and size in the lungs of WT and class I−/− mice. In both types of mice, each lesion was composed of lightly stained and heavily stained areas known from previous studies 20 to represent collections of macrophages and lymphocytes, respectively. The lightly and densely stained areas are also evident from low power micrographs of sections stained for NOS2 by immunocytochemistry. This is shown in Fig. 9, where it can be seen that cells that stained positively for NOS2 in the lung lesions of WT and class I−/− mice were confined to the lightly stained macrophage areas of lesions. At higher power (Fig. 9), these cells were seen to be epithelioid macrophages with a foamy cytoplasm. Acid-fast staining showed that NOS2-positive macrophages contained Mtb bacilli, and that more bacilli were present in macrophages of class I−/− mice than in macrophages of WT mice. This is in keeping with higher level of lung infection in the former mice, in agreement with growth curves shown in a preceding section. Thus, in the lungs both of WT and class I−/− mice the histological response at each site of infection consisted of a localized alveolitis dominated by NOS2-positive macrophages and by lymphocytes. Examination of numerous sections indicated that at day 80 of infection, the lung lesions in class I−/− mice were somewhat larger than in WT mice. This was also evident from macroscopic examination of whole lungs at the time of sacrifice.


The relative importance of T cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice.

Mogues T, Goodrich ME, Ryan L, LaCourse R, North RJ - J. Exp. Med. (2001)

Low power (×25) and high power (×550) micrographs of lung sections of a WT (a and b), class I−/− (c and d), class II−/− (e and f), and TCR-α/β−/− mouse (g and h) stained for NOS2 by immunocytochemistry. At low power, the immunocytochemical reaction product is seen to be located in cells in the lightly stained macrophage areas of the lesions of WT and class I−/− mice. In class II−/− and TCR-α/β−/− mice, the reaction product is scattered in smaller quantity in cells throughout the lesions. At high power, the reaction product is seen confined to macrophages in lesions of WT and class I−/− mice, with some of the macrophages containing acid-fast bacilli. The NOS2-positive macrophages of the class I−/− mouse contain more acid-fast bacilli than NOS2-positive macrophages in WT lesion. In the lesion of the class II−/− mouse, NOS2-positive macrophages are heavily infected with Mtb, although some heavily infected macrophages have little or no reaction product. In the lesion of the TCR-α/β−/− mouse, most of the NOS2 reaction product appears to be concentrated in scattered mononuclear cells.
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Figure 9: Low power (×25) and high power (×550) micrographs of lung sections of a WT (a and b), class I−/− (c and d), class II−/− (e and f), and TCR-α/β−/− mouse (g and h) stained for NOS2 by immunocytochemistry. At low power, the immunocytochemical reaction product is seen to be located in cells in the lightly stained macrophage areas of the lesions of WT and class I−/− mice. In class II−/− and TCR-α/β−/− mice, the reaction product is scattered in smaller quantity in cells throughout the lesions. At high power, the reaction product is seen confined to macrophages in lesions of WT and class I−/− mice, with some of the macrophages containing acid-fast bacilli. The NOS2-positive macrophages of the class I−/− mouse contain more acid-fast bacilli than NOS2-positive macrophages in WT lesion. In the lesion of the class II−/− mouse, NOS2-positive macrophages are heavily infected with Mtb, although some heavily infected macrophages have little or no reaction product. In the lesion of the TCR-α/β−/− mouse, most of the NOS2 reaction product appears to be concentrated in scattered mononuclear cells.
Mentions: Histology was performed on lungs harvested on day 50 and day 80 of infection when infection in WT mice was being held in stationary phase by acquired immunity. However, only day 50 histology is shown, because certain mutant mice were dead by day 80. In mice that survived, day 80 histology was essentially the same as that seen at day 50, except that the lesions were somewhat larger. Low power microscopy of day 50 lung sections (Fig. 8) serve to show the size of individual lesions and the extent to which infection-induced pathology occupied the lungs. For example, it can be seen in Fig. 8 that infection-induced pathology was confined to discrete sites that were similar in appearance, number, and size in the lungs of WT and class I−/− mice. In both types of mice, each lesion was composed of lightly stained and heavily stained areas known from previous studies 20 to represent collections of macrophages and lymphocytes, respectively. The lightly and densely stained areas are also evident from low power micrographs of sections stained for NOS2 by immunocytochemistry. This is shown in Fig. 9, where it can be seen that cells that stained positively for NOS2 in the lung lesions of WT and class I−/− mice were confined to the lightly stained macrophage areas of lesions. At higher power (Fig. 9), these cells were seen to be epithelioid macrophages with a foamy cytoplasm. Acid-fast staining showed that NOS2-positive macrophages contained Mtb bacilli, and that more bacilli were present in macrophages of class I−/− mice than in macrophages of WT mice. This is in keeping with higher level of lung infection in the former mice, in agreement with growth curves shown in a preceding section. Thus, in the lungs both of WT and class I−/− mice the histological response at each site of infection consisted of a localized alveolitis dominated by NOS2-positive macrophages and by lymphocytes. Examination of numerous sections indicated that at day 80 of infection, the lung lesions in class I−/− mice were somewhat larger than in WT mice. This was also evident from macroscopic examination of whole lungs at the time of sacrifice.

Bottom Line: This was associated with the development of a macrophage-dominated alveolitis at sites of infection, with increased synthesis of IFN-gamma and NOS2 mRNA, and with an median survival time (MST) of 258.5 d.In the absence of CD4-mediated immunity (class II(-/-) mice), progressive bacterial growth continued in the lungs and in other organs beyond day 20, resulting in an MST of 77 d.By contrast, in the absence of CD8 T cell-mediated immunity, lung infection was controlled at a 1 log higher stationary level that induced a similar histopathologic response to that of WT mice, and resulted in an MST of 232 d.

View Article: PubMed Central - PubMed

Affiliation: The Trudeau Institute, Saranac Lake, New York 12983, USA.

ABSTRACT
Wild-type (WT) and targeted-mutant mice incapable of making alphabeta T cells, gammadelta T cells, class I major histocompatibility complex (MHC), class II MHC, interferon (IFN)-gamma, or inducible nitric oxide synthase (NOS2), were infected with Mycobacterium tuberculosis (Mtb) by aerosol, and monitored over time for their ability to (a) control infection, (b) develop histopathology at sites of infection, and (c) survive. WT mice acquired the ability to control and to hold infection at a stationary level from day 20 on. This was associated with the development of a macrophage-dominated alveolitis at sites of infection, with increased synthesis of IFN-gamma and NOS2 mRNA, and with an median survival time (MST) of 258.5 d. In the absence of alphabeta T cells, Mtb grew progressively and rapidly to induce a necrotic, neutrophil-dominated lung pathology that killed mice with an MST of 48 d. In the absence of CD4-mediated immunity (class II(-/-) mice), progressive bacterial growth continued in the lungs and in other organs beyond day 20, resulting in an MST of 77 d. By contrast, in the absence of CD8 T cell-mediated immunity, lung infection was controlled at a 1 log higher stationary level that induced a similar histopathologic response to that of WT mice, and resulted in an MST of 232 d.

Show MeSH
Related in: MedlinePlus