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

作者：Hannah Priyadarshini Gideon, Jia Yao Phuah, Amy J. Myers, Bryan D. Bryson, MARK A. RODGERS, M. Teresa Coleman, Pauline A Maiello, Tara Rutledge, Simeone Marino, Sarah M. Fortune, Denise E. Kirschner, Philana Ling Lin, JoAnne L. Flynn · 发表于：PLoS Pathogens · 年份：2015 · DOI：10.1371/journal.ppat.1004603 · 被引用次数：356 · 研究领域：Mycobacterium research and diagnosis、Tuberculosis Research and Epidemiology、Inflammatory Bowel Disease

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, o...