Infection of Mice with Mycobacterium avium Primes CD8+ Lymphocytes for Apoptosis upon Exposure to Macrophages

doi:10.1006/clim.2001.5037

Clinical Immunology

Volume 99, Issue 3, June 2001, Pages 378-386

https://doi.org/10.1006/clim.2001.5037 Get rights and content

Abstract

Mycobacterial infection is associated with granuloma formation in which the presence of apoptosis has been recognized. The role of CD4⁺ T and CD8⁺ T cells in host protection against mycobacterial infections has been demonstrated. Previous studies, however, have shown that CD8⁺ T cells have a limited role in host defense against Mycobacterium avium infection, and we hypothesize that M. avium infection could lead to T cell apoptosis. To investigate this hypothesis, C57BL/6 mice were infected with M. avium strain 101, and the rate of apoptosis of splenic lymphocytes cultured ex vivo with peritoneal macrophages was determined and compared with that of controls. When exposed to infected macrophages ex vivo, splenic lymphocytes from M. avium-infected mice underwent apoptosis, as determined by the TUNEL assay. This increased T cell apoptosis above the control level was observed after 3 weeks but not after only 1 week of infection in mice. No splenic T cell apoptosis was observed when lymphocytes from Mycobacterium smegmatis-infected mice were cultured in the presence of M. smegmatis-infected peritoneal macrophages. Likewise, macrophages infected in vitro with heat-killed M. avium did not trigger T cell apoptosis. Culture of macrophages in different chamber from lymphocytes, separated by a transwell membrane, was not associated with increase of apoptosis compared with uninfected control, suggesting a requirement for direct cell–cell interactions to trigger lymphocyte apoptosis. Using a double staining TUNEL followed by anti-mouse CD4 or anti-mouse CD8 monoclonal antibodies, it was observed that only CD8⁺ T cells but not CD4⁺ T cells underwent apoptosis at 3 weeks of infection. In conclusion, M. avium infection in C57/BL6 mice for 3 weeks renders CD8⁺ T cells prone to apoptosis when exposed ex vivo to macrophages infected with M. avium.

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M. avium infected mice have a high level of CD8+ T cell apoptosis in vitro compared to uninfected mice (Zhong et al., 2003). When in direct contact with infected macrophages, CD8+ T cells from M. avium-infected mice undergo apoptosis (Roger and Bermudez, 2001). In sheep with multibacillary lesions (which are packed with MAP) the ratio of CD4+ T cells/CD8+ T cells is greater than one.
Ovine Johne's disease (OJD) is a degenerative wasting condition of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP). Similar to other pathogenic mycobacterial infections it is a slow-progressing chronic disease and subclinically infected individuals can spread the disease while appearing healthy. MAP infects macrophages and the host responds by mounting a cell-mediated immune response. Disease progression is associated with immune dysfunction but the reasons are unknown. Increasing our current knowledge of the immunological mechanisms involved in disease progression, including apoptotic responses, may allow advancements in the area of early diagnosis, identification of resistant animals and disease control. We describe lymphocyte apoptosis in peripheral blood mononuclear cells (PBMC) and lymph node cells from sheep exposed to MAP as well as from healthy non-exposed sheep. Apoptosis in intestinal lymph node cells from MAP-exposed infected sheep, but not in MAP-exposed uninfected sheep, increased in response to MAP antigen. In this first longitudinal study of lymphocyte apoptosis using an experimental infection model of MAP infection, we found that there was a transient increase of ex vivo PBMC apoptosis in MAP-exposed sheep soon after exposure to MAP (4 months post inoculation). MAP antigen-specific apoptosis occurred later, at 12 months post inoculation. The cells involved were mainly γδ and CD4⁺ T cells. Antigen-mediated lymphocyte apoptosis during mycobacterial disease progression could contribute to the immune dysfunction in Johne's disease.
Apoptosis triggered by Rv1818c, a PE family gene from Mycobacterium tuberculosis is regulated by mitochondrial intermediates in T cells
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T-cell apoptosis is considered to be an important regulatory mechanism of the immune response and is involved in the loss of effector functions during many infectious diseases. In addition, recent studies reported that infection with the pathogens M. tuberculosis or M. avium leads to a downregulation of cell-mediated immunity associated with the induction of CD4+ CD8+ and γδ T-cell apoptosis as well as drastic depletion of CD3 + T cells [6,17–19]. However the precise mechanisms by which mycobacterial antigens induce T-cell apoptosis remain to be elucidated.
Ectopic expression of the Mycobacterium tuberculosis PE-family gene Rv1818c, triggers apoptosis in the mammalian Jurkat T cells, which is blocked by anti-apoptotic protein Bcl-2. Although complete overlap is not observed, a considerable proportion of cellular pools of ectopically expressed Rv1818c localizes to mitochondria. However, recombinant Rv1818c does not trigger release of cytochrome c from isolated mitochondria even though Rv1818c protein induced apoptosis of Jurkat T cells. Apoptosis induced by Rv1818c is blocked by the broad-spectrum caspase inhibitory peptide zVAD-FMK. Unexpectedly, Rv1818c-induced apoptosis is not blocked in a Jurkat sub-clone deficient for caspase-8 (JI 9.2) or in cells where caspase-9 function is inhibited or expression of caspase-9 reduced by siRNA, arguing against a central role for these caspases in Rv1818c-induced apoptotic signaling. Depleting cellular pools of the mitochondrial protein Smac/DIABLO substantially reduces apoptosis consistent with mitochondrial involvement in this death pathway. We present evidence that Rv1818c-induced apoptosis is blocked by the co-transfection of an endogenous inhibitor of caspase activation, XIAP in T cells. Additionally, Rv1818c is released into extracellular environment via exosomes secreted by M. tuberculosis infected BM-DC's and macrophages. Furthermore, the extracellular Rv1818c protein can be detected in T cells co-cultured with infected BM-DC's. Taken together, these data suggest that Rv1818c-induced apoptotic signaling is likely regulated in part by the Smac-dependent activation of caspases in T cells.
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^☆: This work was supported by Contract No. NOI-AI25140 of the National Institute of Allergy and Infectious Diseases and by the Pathogenesis of M. avium Grant from the Foundation for Microbiology. Dr. Roger was supported by a grant from the Banque Populaire de la Côte d'Azur, France.

¹: Current address: Service des Maladies Infectieuses et Tropicales, Hôpital de l'Archet I, Centre Hospitalo-Universitaire de Nice, BP79, 06202, France.

²: To whom correspondence should be addressed at the Kuzell Institute for Arthritis and Infectious Diseases, 2200 Webster Street, San Francisco, CA 94115. Fax: (415) 441-8548. E-mail: [email protected].

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Regular ArticleInfection of Mice with Mycobacterium avium Primes CD8+ Lymphocytes for Apoptosis upon Exposure to Macrophages☆

Abstract

Clin. Immunol. Immunopathol.

Immunobiology

Curr. Opin. Immunol.

Altered natural history of AIDS-related opportunistic infections in the era of potent combination antiretroviral therapy

AIDS

Incidence of Mycobacterium avium–intracellulare complex bacteremia in human immunodeficiency virus-positive patients

J. Infect. Dis.

Disseminated Mycobacterium avium complex disease in the Swiss HIV Cohort Study: Increasing incidence, unchanged prognosis

AIDS

Defects in cell-mediated immunity affect chronic, but not innate, resistance of mice to Mycobacterium avium infection

J. Immunol.

The Mycobacterium avium complex

Clin. Microbiol. Rev.

Production of transforming growth factor-beta by Mycobacterium avium-infected human macrophages is associated with unresponsiveness to IFN-gamma

J. Immunol.

T-cell-independent granuloma formation in response to Mycobacterium avium: Role of tumour necrosis factor-alpha and interferon-gamma

Immunology

IL-6 produced by macrophages infected with Mycobacterium species suppresses T cell responses

J. Immunol.

Growth within macrophages increases the efficiency of Mycobacterium avium in invading other macrophages by a complement receptor-independent pathway

Infect. Immun.

Apoptosis of human monocytes and macrophages by Mycobacterium avium sonicate

Infect. Immun.

Effects of mycobacteria on regulation of apoptosis in mononuclear phagocytes

Infect. Immun.

Homeostasis and self-tolerance in the immune system: Turning lymphocytes off

Science

Anergy, IFN-gamma production, and apoptosis in terminal infection of mice with Mycobacterium avium

J. Immunol.

Ineffective cellular immune response associated with T-cell apoptosis in susceptible Mycobacterium bovis BCG-infected mice

Infect. Immun.

Production of TNF-alpha, IL-6 and TGF-beta, and expression of receptors for TNF-alpha and IL-6, during murine Mycobacterium avium infection

Immunology

Regular Article
Infection of Mice with Mycobacterium avium Primes CD8⁺ Lymphocytes for Apoptosis upon Exposure to Macrophages☆