T cell transcription factor expression evolves over time in granulomas from Mycobacterium tuberculosis-infected cynomolgus macaques
Nicole L. Grant,
Pauline Maiello,
Edwin Klein,
Philana Ling Lin,
H. Jacob Borish,
Jaime Tomko,
L. James Frye,
Alexander G. White,
Denise E. Kirschner,
Joshua T. Mattila,
JoAnne L. Flynn
Affiliations
Nicole L. Grant
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
Pauline Maiello
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
Edwin Klein
Division of Laboratory Animal Research, University of Pittsburgh, Pittsburgh, PA, USA
Philana Ling Lin
Department of Pediatrics, Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA
H. Jacob Borish
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
Jaime Tomko
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
L. James Frye
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
Alexander G. White
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
Denise E. Kirschner
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA
Joshua T. Mattila
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA
JoAnne L. Flynn
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA; Corresponding author
Summary: Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a global health concern, yearly resulting in 10 million new cases of active TB. Immunologic investigation of lung granulomas is essential for understanding host control of bacterial replication. Here, we identify and compare the pathological, cellular, and functional differences in granulomas at 4, 12, and 20 weeks post-infection in Chinese cynomolgus macaques. Original granulomas differ in transcription-factor expression within adaptive lymphocytes, with those at 12 weeks showing higher frequencies of CD8+T-bet+ T cells, while CD4+T-bet+ T cells increase at 20 weeks post-infection. The appearance of T-bet+ adaptive T cells at 12 and 20 weeks is coincident with a reduction in bacterial burden, suggesting their critical role in Mtb control. This study highlights the evolution of T cell responses within lung granulomas, suggesting that vaccines promoting the development and migration of T-bet+ T cells would enhance mycobacterial control.
