Zhidong Hu1,2, Hui-Min Zhao1, Chun-Ling Li3, Xu-Hui Liu1,2, Daniel Barkan4, Douglas B Lowrie1,2, Shui-Hua Lu1,2,3, Xiao-Yong Fan1,2,3. 1. Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University. 2. TB Center, Shanghai Emerging and Reemerging Infectious Disease Institute, Shanghai. 3. School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China. 4. Koret School of Veterinary Medicine, Hebrew University, Rehovot, Israel.
Abstract
Background: KLRG1 is a marker of terminally differentiated CD8+ T cells in viral infection, but its role in human Mycobacterium tuberculosis infection remains elusive. Methods: A set of cohorts of patients with tuberculosis was designed, and the expression profiles and functions of KLRG1+CD4+ T cells were determined with and without antibody blocking. Results: KLRG1 expression on CD4+ T cells was significantly increased in patients with active tuberculosis, compared with healthy controls and patients without tuberculosis. Upon M. tuberculosis-specific stimulation, the ability to secrete interferon γ, interleukin 2, and tumor necrosis factor α was significantly greater in KLRG1-expressing CD4+ T cells than in their KLRG-negative counterparts and was accompanied by a decreased proportion of regulatory T cells and increased Akt signaling. However, KLRG1-expressing CD4+ T cells had a shorter life-span, which was associated with a higher apoptosis rate but a similar proliferative response. Blockade of KLRG1 signaling significantly enhanced interferon γ and interleukin 2 secretion without affecting either cell apoptosis or multiplication. Addition of a specific Akt inhibitor prevented this increased cytokine response, implicating the Akt signaling pathway. Conclusions: Our study delineated the profile of KLRG1+CD4+ T cells in patients with tuberculosis and suggests that M. tuberculosis infection drives CD4+ T cells to acquire increased effector function in a terminally differentiated state, which is restrained by KLRG1 via KLRG1/Akt signaling pathway.
Background: KLRG1 is a marker of terminally differentiated CD8+ T cells in viral infection, but its role in human Mycobacterium tuberculosis infection remains elusive. Methods: A set of cohorts of patients with tuberculosis was designed, and the expression profiles and functions of KLRG1+CD4+ T cells were determined with and without antibody blocking. Results:KLRG1 expression on CD4+ T cells was significantly increased in patients with active tuberculosis, compared with healthy controls and patients without tuberculosis. Upon M. tuberculosis-specific stimulation, the ability to secrete interferon γ, interleukin 2, and tumor necrosis factor α was significantly greater in KLRG1-expressing CD4+ T cells than in their KLRG-negative counterparts and was accompanied by a decreased proportion of regulatory T cells and increased Akt signaling. However, KLRG1-expressing CD4+ T cells had a shorter life-span, which was associated with a higher apoptosis rate but a similar proliferative response. Blockade of KLRG1 signaling significantly enhanced interferon γ and interleukin 2 secretion without affecting either cell apoptosis or multiplication. Addition of a specific Akt inhibitor prevented this increased cytokine response, implicating the Akt signaling pathway. Conclusions: Our study delineated the profile of KLRG1+CD4+ T cells in patients with tuberculosis and suggests that M. tuberculosis infection drives CD4+ T cells to acquire increased effector function in a terminally differentiated state, which is restrained by KLRG1 via KLRG1/Akt signaling pathway.
Authors: Zhen-Yan Chen; Lei Wang; Ling Gu; Rong Qu; Douglas B Lowrie; Zhidong Hu; Wei Sha; Xiao-Yong Fan Journal: Front Microbiol Date: 2020-08-07 Impact factor: 5.640
Authors: Robert J Wilkinson; Catherine Riou; Elsa Du Bruyn; Sheena Ruzive; Cecilia S Lindestam Arlehamn; Alessandro Sette; Alan Sher; Daniel L Barber Journal: Mucosal Immunol Date: 2020-07-16 Impact factor: 7.313