Age dependent increase in early resistance of mice to Mycobacterium tuberculosis is associated with an increase in CD8 T cells that are capable of antigen independent IFN-γ production

ABSTRACT The host immune response is generally sufficient to contain Mycobacterium tuberculosis infection. It does not, however, efficiently prevent subsequent infection with M. tuberculosis or provide sterilizing immunity. While the understanding of the immune response generated against this pathogen is incomplete, improvements have been achieved due to advances in immunological tools. In this study, we analyzed the multifunctional nature of primary and memory CD8 T-cell responses generated during murine M. tuberculosis infection. We generated a recombinant M. tuberculosis strain expressing ovalbumin (OVA) epitopes in order to expand the peptides for the detection of CD8 T cells during M. tuberculosis infection and enable us to use OVA-specific reagents. Our results indicate that the majority of M. tuberculosis-specific CD8 T cells are limited to either cytotoxicity or the secretion of gamma interferon (IFN-γ), with cytotoxicity being far more prevalent than IFN-γ secretion. Memory CD8 T cells responded earlier and reached higher levels in the lungs than naïve CD8 T cells, as was expected. They were, however, less cytotoxic and secreted less IFN-γ than newly primed CD8 T cells, suggesting that one factor contributing to bacterial persistence and lack of sterilizing immunity may be the low quality of memory cells that are generated.

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Induction of Mycobacterium tuberculosis-Specific Primary and Secondary T-Cell Responses in Interleukin-15-Deficient Mice

Infection and Immunity ◽

10.1128/iai.73.5.2910-2922.2005 ◽

2005 ◽

Vol 73 (5) ◽

pp. 2910-2922 ◽

Cited By ~ 30

Author(s):

Vanja Lazarevic ◽

David J. Yankura ◽

Sherrie J. Divito ◽

JoAnne L. Flynn

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

T Cell ◽

Cd8 T Cells ◽

T Cell Responses ◽

Effector T Cells ◽

Cell Responses ◽

Interleukin 15 ◽

Ifn Γ ◽

Deficient Mice

ABSTRACT Several studies have provided evidence that interleukin-15 (IL-15) can enhance protective immune responses against Mycobacterium tuberculosis infection. However, the effects of IL-15 deficiency on the functionality of M. tuberculosis-specific CD4 and CD8 T cells are unknown. In this study, we investigated the generation and maintenance of effector and memory T-cell responses following M. tuberculosis infection of IL-15−/− mice. IL-15−/− mice had slightly higher bacterial numbers during chronic infection, which were accompanied by an increase in gamma interferon (IFN-γ)-producing CD4 and CD8 T cells. There was no evidence of increased apoptosis or a defect in proliferation of CD8 effector T cells following M. tuberculosis infection. The induction of cytotoxic and IFN-γ CD8 T-cell responses was normal in the absence of IL-15 signaling. The infiltration of CD4 and CD8 T cells into the lungs of “immune” IL-15−/− mice was delayed in response to M. tuberculosis challenge. These findings demonstrate that efficient effector CD4 and CD8 T cells can be developed following M. tuberculosis infection in the absence of IL-15 but that recall T-cell responses may be impaired.

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Immunogenicity Test of ESAT-6/CFP-10 Mycobacterium Tuberculosis (Indonesian Strain) Recombinant Protein Fusion: IFN-γ and CD8+ T Cells Expression in PBMC Culture

Jurnal Respirologi Indonesia ◽

10.36497/jri.v38i4.44 ◽

2019 ◽

Vol 38 (4) ◽

pp. 210-8

Author(s):

Anung Sri Handayani ◽

Tri Wahju Astuti ◽

Teguh Rahayu Sartono ◽

Maimun Zulhaidah Arthamin ◽

Fransisca Srioetami Tanoerahardjo

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

Recombinant Protein ◽

Healthy Subject ◽

Cd8 T Cells ◽

Vaccine Development ◽

Laboratory Research ◽

Protein Fusion ◽

Pbmc Culture ◽

Ifn Γ

Background: BCG vaccination is one way to control tuberculosis (TB) but still poor in efficacy thus new vaccine development is needed. Immunogenicity test is needed in developing new vaccine. The aim of this study was to understand whether the recombinant protein fusion of ESAT-6/CFP-10 Mycobacterium tuberculosis (M. tuberculosis) can stimulate cellular immune response, especially IFN-γ and CD8 + T cell expression in PBMC cultures. Methods: This study was an experimental laboratory research conducted on PBMC cultures of 3 groups of subjects (TB patients, latent TB patients and healthy subjects) at RSUD Dr. Saiful Anwar in April-July 2017. The sample of each groups was 8 subjects. Each groups induced by recombinant protein fusion ESAT-6/CFP-10 M. tuberculosis as a standard protocol and to establish the immunogenicity status. CD8+ T cells IFN-γ expressed by C8+ were measured by flowcytometry. Result: Recombinant protein fusion ESAT-6/CFP-10 can stimulate CD8+ T cells and IFN-γ expressed by CD8+ T cells in all group. The highest stimulation of CD8+ percentage was found in healthy subject (37.533 ± 7.264) and IFN-γ expressed by CD8+ T cells was found in healthy subject (7.908 ± 4.457); There are increase significantly CD8+ T cells (p=0.001) and IFN-γ expressed by CD8+ T cells (p=0.217) not significantly in healthy subject compared in PPD and without antigen. Conclusion: Recombinant protein fusion ESAT-6/CFP-10 M. tuberculosis can stimulate CD8+ T cells and IFN-γ expressed by CD8+ T cells in healthy subject. Recombinant protein fusion ESAT-6/CFP-10 M. tuberculosis potential as a new vaccine candidate. (J Respir Indo. 2018;38: 210-8)

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Th1 Cytokines Facilitate CD8-T-Cell-Mediated Early Resistance to Infection with Mycobacterium tuberculosis in Old Mice

Infection and Immunity ◽

10.1128/iai.01475-05 ◽

2006 ◽

Vol 74 (6) ◽

pp. 3314-3324 ◽

Cited By ~ 23

Author(s):

Bridget Vesosky ◽

David K. Flaherty ◽

Joanne Turner

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

T Cell ◽

Infectious Diseases ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

Cell Phenotype ◽

Ifn Γ ◽

Th1 Cytokines ◽

Old Mice

ABSTRACT Numerous immunological defects begin to emerge as an individual ages, the consequence of which is heightened susceptibility to infectious diseases. Despite this decline in immune function, old mice display an early transient resistance to Mycobacterium tuberculosis infection in the lung, which is dependent on CD8 T cells and gamma interferon (IFN-γ) production. In this study, we investigated the mechanism of resistance by examining the CD8-T-cell phenotype and function in old naïve and M. tuberculosis-infected mice. Pulmonary CD8 T cells from naïve old mice expressed cell surface markers of memory in addition to receptors for several Th1 cytokines. Stimulation of lung cells from naïve old mice with a combination of Th1 cytokines (interleukin-2 [IL-2], IL-12, and IL-18) resulted in nonspecific production of IFN-γ by memory CD8 T cells. Following aerosol infection with M. tuberculosis, the lungs of old mice contained significantly more IL-12, IL-18, and IFN-γ than the lungs of young mice contained. Together, these data demonstrate that the increased and early production of Th1 cytokines in the lungs of M. tuberculosis-infected old mice, in combination with CD8 T cells that can nonspecifically produce IFN-γ, leads to transient control of M. tuberculosis growth in the lungs of old mice. Further characterization of this mechanism should provide essential information regarding the aging immune system and should contribute to the development of novel strategies to decrease the morbidity and mortality of the aging population associated with infectious diseases.

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CD8 T Cells in Old Mice Contribute to the Innate Immune Response to Mycobacterium tuberculosis via Interleukin-12p70-Dependent and Antigen-Independent Production of Gamma Interferon

Infection and Immunity ◽

10.1128/iai.00295-09 ◽

2009 ◽

Vol 77 (8) ◽

pp. 3355-3363 ◽

Cited By ~ 12

Author(s):

Bridget Vesosky ◽

Erin K. Rottinghaus ◽

Craig Davis ◽

Joanne Turner

Keyword(s):

Immune Response ◽

T Cells ◽

Mycobacterium Tuberculosis ◽

Cd8 T Cells ◽

The Elderly ◽

Gamma Interferon ◽

Ifn Γ ◽

Aerosol Infection ◽

Old Mice

ABSTRACT Elderly individuals have increased morbidity and mortality associated with infectious diseases due in part to the progressive age-associated decline in immune function. Despite this, the old mouse model of Mycobacterium tuberculosis infection has revealed a CD8- and gamma interferon (IFN-γ)-dependent early resistance to infection. In this study, we investigated the mechanism by which CD8 T cells from old mice contributed to the early immune response to M. tuberculosis. Following a low-dose aerosol infection with M. tuberculosis, CD8 T cells were identified as being a dominant source of IFN-γ expression in the lungs of old mice early after infection, before the typical onset of antigen-specific immunity. In addition, M. tuberculosis-induced IFN-γ production by CD8 T cells isolated from naïve old mice was major histocompatibility complex class I independent but was dependent on interleukin-12p70, confirming an innate role of CD8 T cells during M. tuberculosis infection. Moreover, the ability of CD8 T cells from old mice to produce increased innate IFN-γ levels in response to M. tuberculosis infection was defined as a unique function of CD8 T cells from old mice and not the aged lung environment. Finally, we have identified increased expression of SET as being one possible mechanism by which CD8 T cells from old mice produce enhanced levels of IFN-γ. Additional characterizations of the signaling events that lead to enhanced innate IFN-γ production by CD8 T cells in old mice may lead to novel strategies to further enhance or perpetuate beneficial immune responses in the elderly.

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Early Emergence of CD8+ T Cells Primed for Production of Type 1 Cytokines in the Lungs of Mycobacterium tuberculosis-Infected Mice

Infection and Immunity ◽

10.1128/iai.67.8.3980-3988.1999 ◽

1999 ◽

Vol 67 (8) ◽

pp. 3980-3988 ◽

Cited By ~ 116

Author(s):

Natalya V. Serbina ◽

JoAnne L. Flynn

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

Cd8 T Cells ◽

Intracellular Cytokine Staining ◽

Short Term ◽

Ifn Γ ◽

Antigen Presenting ◽

Kinetics Of

ABSTRACT Several lines of evidence suggest that CD8 T cells are important in protection against tuberculosis. To understand the function of this cell population in the immune response against Mycobacterium tuberculosis, T cells from lungs of M. tuberculosis-infected mice were examined by flow cytometry. The kinetics of the appearance of CD8 T cells in lungs of infected mice closely paralleled that of CD4 T cells. Both CD4+ and CD8+ T cells displaying an activated phenotype were found in the lungs as early as 1 week postinfection. By 2 weeks, total cell numbers in the lungs had tripled and percentages of T cells were increased two- to threefold; the percentages of CD4+ T cells were ca. twofold higher than those of CD8+ T cells. Short-term stimulation with M. tuberculosis-infected antigen-presenting cells induced cytokine production by primed CD4+ and CD8+ T cells. Intracellular cytokine staining revealed that 30% ± 5% of CD4+ and 23% ± 4% of CD8+ T cells were primed for production of gamma interferon (IFN-γ). However, a difference in in vivo IFN-γ production by T cells was observed with ∼12% of CD4+ T cells and ∼5% of CD8+ T cells secreting cytokine in the lungs at any given time during infection. The data presented indicate that although early in infection the majority of IFN-γ is produced by CD4+ T cells, cytokine-producing CD8+ T cells are readily available when triggered by the appropriate stimuli.

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