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Variability in Tuberculosis Granuloma T Cell Responses Exists, but a Balance of Pro- and Anti-inflammatory Cytokines Is Associated with Sterilization

Gideon, HP and Phuah, JY and Myers, AJ and Bryson, BD and Rodgers, MA and Coleman, MT and Maiello, P and Rutledge, T and Marino, S and Fortune, SM and Kirschner, DE and Lin, PL and Flynn, JAL (2015) Variability in Tuberculosis Granuloma T Cell Responses Exists, but a Balance of Pro- and Anti-inflammatory Cytokines Is Associated with Sterilization. PLoS Pathogens, 11 (1). 1 - 28. ISSN 1553-7366

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Abstract

© 2015 Gideon et al. Lung granulomas are the pathologic hallmark of tuberculosis (TB). T cells are a major cellular component of TB lung granulomas and are known to play an important role in containment of Mycobacterium tuberculosis (Mtb) infection. We used cynomolgus macaques, a non-human primate model that recapitulates human TB with clinically active disease, latent infection or early infection, to understand functional characteristics and dynamics of T cells in individual granulomas. We sought to correlate T cell cytokine response and bacterial burden of each granuloma, as well as granuloma and systemic responses in individual animals. Our results support that each granuloma within an individual host is independent with respect to total cell numbers, proportion of T cells, pattern of cytokine response, and bacterial burden. The spectrum of these components overlaps greatly amongst animals with different clinical status, indicating that a diversity of granulomas exists within an individual host. On average only about 8% of T cells from granulomas respond with cytokine production after stimulation with Mtb specific antigens, and few “multi-functional” T cells were observed. However, granulomas were found to be “multi-functional” with respect to the combinations of functional T cells that were identified among lesions from individual animals. Although the responses generally overlapped, sterile granulomas had modestly higher frequencies of T cells making IL-17, TNF and any of T-1 (IFN-γ, IL-2, or TNF) and/or T-17 (IL-17) cytokines than non-sterile granulomas. An inverse correlation was observed between bacterial burden with TNF and T-1/T-17 responses in individual granulomas, and a combinatorial analysis of pair-wise cytokine responses indicated that granulomas with T cells producing both pro- and anti-inflammatory cytokines (e.g. IL-10 and IL-17) were associated with clearance of Mtb. Preliminary evaluation suggests that systemic responses in the blood do not accurately reflect local T cell responses within granulomas.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Gideon, HP
Phuah, JY
Myers, AJ
Bryson, BD
Rodgers, MAmar118@pitt.eduMAR118
Coleman, MT
Maiello, P
Rutledge, Ttar36@pitt.eduTAR36
Marino, S
Fortune, SM
Kirschner, DE
Lin, PLpll7@pitt.eduPLL7
Flynn, JAL
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorLewinsohn, David M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 January 2015
Date Type: Publication
Journal or Publication Title: PLoS Pathogens
Volume: 11
Number: 1
Page Range: 1 - 28
DOI or Unique Handle: 10.1371/journal.ppat.1004603
Schools and Programs: School of Medicine > Microbiology and Molecular Genetics
School of Medicine > Pediatrics
School of Medicine > Radiology
Refereed: Yes
ISSN: 1553-7366
Other ID: NLM PMC4303275
PubMed Central ID: PMC4303275
PubMed ID: 25611466
Date Deposited: 12 May 2015 19:44
Last Modified: 13 Oct 2017 23:56
URI: http://d-scholarship.pitt.edu/id/eprint/24081

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