Limited frequency of cytokine-producing T cells in tuberculosis lung granulomas (MPF6P.736)

Lung granulomas are the pathologic hallmark of Tuberculosis (TB). T cells are a major cellular component of tuberculosis lung granulomas and are known to play an important role in containment and progression of Mtb infection. We used cynomolgus macaques, a non-human primate model that recapitulates human TB, with clinically active disease and latent infection, to understand the functional characteristics and dynamics of T cells in individual granulomas and to correlate T cell cytokine response of granulomas to its bacterial burden and its systemic response. Our results suggest 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 various clinical status of these animals, indicating that a diversity of granulomas exist in individual hosts. Multi-parametric flow cytometry analysis of functional T cells in granulomas suggests that on average only ~6% of T cells respond to Mtb antigens with production of Th1/Th17 or IL-10 cytokines. An inverse correlation was observed between bacterial burden and Th1/Th17 response in individual granulomas. The systemic responses do not accurately reflect responses in granulomas, and suggests that, especially in active TB, the blood is a negative reflection of granuloma responses. Overall, these data provide insight into the local and systemic responses in tuberculosis.