Notch 2 receptor expression and reduced cytotoxicity in MAIT cells of active pulmonary TB patients
Pimpayao Sodsai,1 Panjana Sengprasert,1 Thitiya Sae-jung,2 Kamon Kawkitinarong,3 Nibondh Udomsantisuk,4 Tanapat Palaga,5 Rangsima Reantragoon1,6
1 Immunology Division, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
2 Medical Microbiology Interdisciplinary Program, Graduate School, Chulalongkorn University, Bangkok, Thailand
3 Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
4 Bacteriology Division, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
5 Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
6 Center of Excellence in Immunology and Immune-mediated Diseases, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Abstract
Background: Tuberculosis (TB) is caused by Mycobacterium tuberculosis (M.tb), resulting in significant increase in mortality rate worldwide. Immunity against M.tb consists of both innate and adaptive immunity, with emerging evidence of the role of the unconventional mucosal-associated invariant T (MAIT) cells. MAIT cells are MR1-restricted T cells that possess anti-bacterial activity, including activity in response to M.tb. To date, human studies regarding peripheral blood MAIT cell frequency and MAIT cell activity in TB patients are still controversial and most studies are cross-sectional.
Objective: To evaluate MAIT cell function and TCR repertoire over the course of anti-TB drug treatment of active pulmonary TB patients.
Methods: MAIT cells isolated from blood of active pulmonary TB patients at various anti-TB drug treatment time points were stimulated with anti-CD3/CD28 or PMA/Ionomycin and evaluated for their cytokine and cytotoxic molecule profile. In parallel, Notch signaling was determined. Clonal analysis of MAIT cells at various anti-TB drug treatment time points was also performed in one individual.
Results: We found that there was reduced perforin and granzyme B production on MAIT cells upon stimulation with PMA/Ionomycin along with decreased cell surface expression of Notch 2 receptor. Notch 2 regulates granzyme B expression in T cells, and this reduction may indicate a similar role of Notch 2 in regulating MAIT cell function. Lastly, MAIT cell diversity with increased non-canonical TRBV usage was highest and observed at 2 months into treatment.
Conclusions: Our study provides preliminary data in understanding MAIT cell function, Notch signaling and TCR repertoire expression in active pulmonary TB patients.
Key words: MAIT cell phenotype, Notch signaling pathway, MAIT TCR repertoire, Active pulmonary TB patients, Anti-TB drug treatment