title: Differentiation of antigen-specific T cells with limited functional capacity during Mycobacterium tuberculosis infection.
abstract: Despite the generation of Mycobacterium tuberculosis-specific T cell immune responses during the course of infection, only 5 to 10% of exposed individuals develop active disease, while others develop a latent infection. This phenomenon suggests defective M. tuberculosis-specific immunity, which necessitates more careful characterization of M. tuberculosis-specific T cell responses. Here, we longitudinally analyzed the phenotypes and functions of M. tuberculosis-specific T cells. In contrast to the functional exhaustion of T cells observed after chronic infection, M. tuberculosis-specific CD8(+) T cells differentiated into either effector (CD127(lo) CD62L(lo)) or effector memory (CD127(hi) CD62L(lo)) cells, but not central memory cells (CD127(hi) CD62L(hi)), with low programmed death 1 (PD-1) expression, even in the presence of high levels of bacteria. Additionally, M. tuberculosis-specific CD8(+) and CD4(+) T cells produced substantial levels of tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ), but not interleukin 2 (IL-2), upon in vitro restimulation. Among M. tuberculosis-specific CD8(+) T cells, CD127(hi) effector memory cells displayed slower ongoing turnover but greater survival potential. In addition, these cells produced more IFN-γ and TNF-α and displayed lytic activity upon antigen stimulation. However, the effector function of M. tuberculosis-specific CD8(+) CD127(hi) effector memory T cells was inferior to that of canonical CD8(+) CD127(hi) memory T cells generated after acute lymphocytic choriomeningitis virus infection. Collectively, our data demonstrate that M. tuberculosis-specific T cells can differentiate into memory T cells during the course of M. tuberculosis infection independent of the bacterial burden but with limited functionality. These results provide a framework for further understanding the mechanisms of M. tuberculosis infection that can be used to develop more effective vaccines.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Yun Hee
authors.initials: YH
authors.lastname: Jeong
authors.forename: Bo-Young
authors.initials: BY
authors.lastname: Jeon
authors.forename: Sun-Hwa
authors.initials: SH
authors.lastname: Gu
authors.forename: Sang-Nae
authors.initials: SN
authors.lastname: Cho
authors.forename: Sung Jae
authors.initials: SJ
authors.lastname: Shin
authors.forename: Jun
authors.initials: J
authors.lastname: Chang
authors.forename: Sang-Jun
authors.initials: SJ
authors.lastname: Ha
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology; D058491:Bacterial Load; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D007111:Immunity, Cellular / Q000276:immunology; D007156:Immunologic Memory / Q000502:physiology; D007371:Interferon-gamma / Q000378:metabolism; D008137:Longitudinal Studies; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010641:Phenotype; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D000943:Antigens, Differentiation; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma