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Cited by 165Tuberculosis Research and EpidemiologyImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

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Characterization of Human CD8+ T Cells Reactive with Mycobacterium tuberculosis–infected Antigen-presenting Cells

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Lewinsohn, David M., Alderson, Mark R., Briden, Andria L., Riddell, Stanley R., Reed, Steven G., Grabstein, Kenneth H.·1998·The Journal of Experimental Medicine
DOI 10.1084/jem.187.10.1633PMC PMC2212289
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Abstract

Previous studies in murine models, including those using the β2 microglobulin knockout mouse, have suggested an important role for CD8+ T cells in host defense to Mycobacterium tuberculosis (Mtb). At present, little is understood about these cells in the human immune response to tuberculosis. This report demonstrates the existence of human Mtb-reactive CD8+ T cells. These cells are present preferentially in persons infected with Mtb and produce interferon γ in response to stimulation with Mtb-infected target cells. Recognition of Mtb-infected cells by these CD8+ T cells is restricted neither by the major histocompatibility complex (MHC) class I A, B, or C alleles nor by CD1, although it is inhibited by anti–MHC class I antibody. The Mtb-specific CD8+ T cells recognize an antigen which is generated in the proteasome, but which does not require transport through the Golgi-ER. The data suggest the possible use of nonpolymorphic MHC class Ib antigen presenting structures other than CD1.

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Figure 1 CD8+ T cell line produces IFN-γ in response to Mtb-infected DCs. A CD8+ T cell line was generated from an Mtb-infected individual using infected DCs as described in Materials and Methods. On day 11, T cell lines were assayed by stimulation with Mtb-infected DCs, and supernatants were collected after 18–24 h. Data represents the mean of triplicate determinations of IFN-γ as determined by ELISA. In this and subsequent experiments, the SD is <5% of the mean.
Figure 1 CD8+ T cell line produces IFN-γ in response to Mtb-infected DCs. A CD8+ T cell line was generated from an Mtb-infected individual using infected DCs as described in Materials and Methods. On day 11, T cell lines were assayed by stimulation with Mtb-infected DCs, and supernatants were collected after 18–24 h. Data represents the mean of triplicate determinations of IFN-γ as determined by ELISA. In this and subsequent experiments, the SD is <5% of the mean.CC BY-NC-SA · PubMed Central
Figure 2 Mtb-reactive CD8+ CTL are found preferentially in individuals infected with Mtb. Mtb-reactive T cell lines were generated and assayed as described in Materials and Methods. Lines were generated from five individuals with evidence of Mtb infection (PPD > 15 mm), and from six individuals with no evidence of Mtb infection (PPD < 5 mm; no history of bacillus Calmette-Guérin vaccination) in three separate experiments. Stimulation index = (Experimental IFN-γ)/(Control IFN-γ). Each tick represents 5 SI units. Positive responses are defined as SI > 5.
Figure 2 Mtb-reactive CD8+ CTL are found preferentially in individuals infected with Mtb. Mtb-reactive T cell lines were generated and assayed as described in Materials and Methods. Lines were generated from five individuals with evidence of Mtb infection (PPD > 15 mm), and from six individuals with no evidence of Mtb infection (PPD < 5 mm; no history of bacillus Calmette-Guérin vaccination) in three separate experiments. Stimulation index = (Experimental IFN-γ)/(Control IFN-γ). Each tick represents 5 SI units. Positive responses are defined as SI > 5.CC BY-NC-SA · PubMed Central
Figure 3 Reciprocal specificity of Mtb-reactive and HIV gp24–reactive T cells. 5 × 104 Mtb-reactive CD8+ T cell clones (23 and 29) and an HLA-B44–restricted HIV p24-specific CD8+ T cells (clone 10D10-82) were incubated with 3 × 104 DCs (autologous to clones 23 and 29; B44-positive) that had been treated for 18 h with Mtb, HLA-B44–restricted HIV p24 peptide 103 (303–322), or LPS (5 μg/ml). Supernatants were collected after 18 h and assessed for the presence of IFN-γ by ELISA. Each tick represents 1000 pg/ml. These data are representative of three experiments.
Figure 3 Reciprocal specificity of Mtb-reactive and HIV gp24–reactive T cells. 5 × 104 Mtb-reactive CD8+ T cell clones (23 and 29) and an HLA-B44–restricted HIV p24-specific CD8+ T cells (clone 10D10-82) were incubated with 3 × 104 DCs (autologous to clones 23 and 29; B44-positive) that had been treated for 18 h with Mtb, HLA-B44–restricted HIV p24 peptide 103 (303–322), or LPS (5 μg/ml). Supernatants were collected after 18 h and assessed for the presence of IFN-γ by ELISA. Each tick represents 1000 pg/ml. These data are representative of three experiments.CC BY-NC-SA · PubMed Central
Figure 4 CD8+ T cell clones recognize M. bovis but not M. avium. CD8+ T cell clone 23 was stimulated with autologous DCs infected with varying numbers of either Mtb (H37Rv), M. bovis, or M. avium. After 18 h, supernatants were collected and assessed for the presence of IFN-γ by ELISA.
Figure 4 CD8+ T cell clones recognize M. bovis but not M. avium. CD8+ T cell clone 23 was stimulated with autologous DCs infected with varying numbers of either Mtb (H37Rv), M. bovis, or M. avium. After 18 h, supernatants were collected and assessed for the presence of IFN-γ by ELISA.CC BY-NC-SA · PubMed Central
Figure 5 Mtb-specific CD8+ T cells are not restricted by a unique HLA-A, -B, or -C allele. CD8+ T cell clones 23 and 29 were stimulated with various DCs that had been Mtb infected or not (control) and fixed with 1% paraformaldahyde before addition to culture. DCs from different HLA-typed donors were used as indicated where D160 is autologous to the clones tested. After 18 h, supernatants were collected and assessed for the presence of IFN-γ by ELISA. This experiment is representative of three such experiments.
Figure 5 Mtb-specific CD8+ T cells are not restricted by a unique HLA-A, -B, or -C allele. CD8+ T cell clones 23 and 29 were stimulated with various DCs that had been Mtb infected or not (control) and fixed with 1% paraformaldahyde before addition to culture. DCs from different HLA-typed donors were used as indicated where D160 is autologous to the clones tested. After 18 h, supernatants were collected and assessed for the presence of IFN-γ by ELISA. This experiment is representative of three such experiments.CC BY-NC-SA · PubMed Central
Figure 6 Anti HLA class I antibody inhibits T cell–dependent generation of IFN-γ. CD8+ T cell clones 23 and 29 were stimulated with Mtb-infected or control DCs in the presence of anti–MHC class I (W6/32; 2 μg/ml), anti–MHC class II (L243; 2 μg/ml), or IgG2a isotype control antibody (2 μg/ml), added at the beginning of the assay. After 18 h, supernatants were collected and assessed for the presence of IFN-γ by ELISA.
Figure 6 Anti HLA class I antibody inhibits T cell–dependent generation of IFN-γ. CD8+ T cell clones 23 and 29 were stimulated with Mtb-infected or control DCs in the presence of anti–MHC class I (W6/32; 2 μg/ml), anti–MHC class II (L243; 2 μg/ml), or IgG2a isotype control antibody (2 μg/ml), added at the beginning of the assay. After 18 h, supernatants were collected and assessed for the presence of IFN-γ by ELISA.CC BY-NC-SA · PubMed Central
Figure 7 Effect of metabolic inhibitors on presentation of Mtb-derived antigen. (A) CD8+ T cell clones 23 and 29 were stimulated with DCs that had been preincubated with metabolic inhibitors, lactacystin (proteasomal degradation; 40 μM), brefeldin A (Golgi-ER transport; 10 μg/ml), chloroquine (endosomal acidification; 100 μM), or cytochalasin D (phagocytosis; 10 μg/ml) for 1 h before the addition of Mtb, and subsequently fixed in 1% paraformaldehyde after 18 h of infection. After 18 h, supernatants were collected and assessed for the presence of IFN-γ by ELISA. This experiment is representative of three such experiments. (B) An influenza matrix peptide–reactive CTL clone was stimulated with DCs that had been preincubated with metabolic inhibitors lactacystin or brefeldin A for 1 h before the addition of live influenza A virus and fixed after 18 h of infection. In the second graph, a PPD-reactive CD4+ T cell clone was stimulated with the APCs described in A. After 18 h, supernatants were collected and assessed for the presence of IFN-γ by ELISA. This experiment is representative of two such experiments.
Figure 7 Effect of metabolic inhibitors on presentation of Mtb-derived antigen. (A) CD8+ T cell clones 23 and 29 were stimulated with DCs that had been preincubated with metabolic inhibitors, lactacystin (proteasomal degradation; 40 μM), brefeldin A (Golgi-ER transport; 10 μg/ml), chloroquine (endosomal acidification; 100 μM), or cytochalasin D (phagocytosis; 10 μg/ml) for 1 h before the addition of Mtb, and subsequently fixed in 1% paraformaldehyde after 18 h of infection. After 18 h, supernatants were collected and assessed for the presence of IFN-γ by ELISA. This experiment is representative of three such experiments. (B) An influenza matrix peptide–reactive CTL clone was stimulated with DCs that had been preincubated with metabolic inhibitors lactacystin or brefeldin A for 1 h before the addition of live influenza A virus and fixed after 18 h of infection. In the second graph, a PPD-reactive CD4+ T cell clone was stimulated with the APCs described in A. After 18 h, supernatants were collected and assessed for the presence of IFN-γ by ELISA. This experiment is representative of two such experiments.CC BY-NC-SA · PubMed Central

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Metadata

Authors
Lewinsohn, D. M., Alderson, M. R., Briden, A. L., Riddell, S. R., Reed, S. G., & Grabstein, K. H.
Affiliations
Infectious Disease Research Institute (US)
Corresponding author
Lewinsohn, David M.
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
1998-05-18
Volume
187
Issue
10
Pages
1633-1640
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.187.10.1633
PMC
PMC2212289
OpenAlex
W2111354206
Cited by
165
References
33
Citations by year
2026: 2 · 2025: 3 · 2022: 3 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 2 · 2016: 6 · 2015: 1 · 2014: 2 · 2013: 1 · 2012: 6
FWCI
16.05
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
National Heart, Lung, and Blood Institute (5T32 HL-07287, T32HL007287)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
CD8+ T cells, Mycobacterium tuberculosis, tuberculosis, interferon-gamma, MHC class I restriction, MHC class Ib, antigen presentation, human immune response
MeSH terms
Acetylcysteine, Amino Acid Sequence, Animals, Chloroquine, Humans, Lymphocyte Cooperation, Molecular Sequence Data, Mycobacterium tuberculosis, Tuberculosis, Cysteine Proteinase Inhibitors, Antigen Presentation, CD8-Positive T-Lymphocytes, Mice

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