title: Variability in tuberculosis granuloma T cell responses exists, but a balance of pro- and anti-inflammatory cytokines is associated with sterilization.
abstract: 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.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Hannah Priyadarshini
authors.initials: HP
authors.lastname: Gideon
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: JiaYao
authors.initials: J
authors.lastname: Phuah
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Myers
authors.affiliation: Department of Immunology and Infectious Disease, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Bryson
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rodgers
authors.affiliation: Department of Radiology, PET Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Coleman
authors.affiliation: Department of Radiology, PET Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Pauline
authors.initials: P
authors.lastname: Maiello
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Tara
authors.initials: T
authors.lastname: Rutledge
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Simeone
authors.initials: S
authors.lastname: Marino
authors.affiliation: Department of Immunology and Infectious Disease, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Fortune
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Denise E
authors.initials: DE
authors.lastname: Kirschner
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Philana Ling
authors.initials: PL
authors.lastname: Lin
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: JoAnne L
authors.initials: JL
authors.lastname: Flynn
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D015769:Granuloma, Respiratory Tract / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D007111:Immunity, Cellular; D007246:Infertility / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D018655:Lymphocyte Count; D008252:Macaca fascicularis; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D014376:Tuberculosis / Q000276:immunology* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators