Abstract
Tuberculosis (TB) is a chronic disease mainly caused by Mycobacterium tuberculosis. The function of T cells usually decreased and even exhausted in severe TB such as multiple drug resistant TB (MDR-TB), which might lead to the failure of treatment in return. The mechanism of T cell dysfunction in TB is still not clear. In this study we set up a mouse model of T cell dysfunction by persistent M. tuberculosis antigen stimulation and investigated the therapeutic role of interleukin 2 (IL-2) in it. C57BL/6 mice were primed with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) and boosted repeatedly with a combination of M. tuberculosis fusion proteins Mtb10.4-HspX (MH) plus ESAT6-Ag85B-MPT64 <190−198>-Mtb8.4-Rv2626c (LT70) or MH plus ESAT6 and CFP10 with adjuvant of N, N′-dimethyl-N, N′-dioctadecylammonium bromide (DDA) plus polyinosinic-polycytidylic acid (Poly I:C). Following persistent antigen stimulation, the mice were treated with IL-2 and the therapeutic effects were analyzed. The results showed that compared with the mice that received transient antigen stimulation (boost twice), persistent antigen stimulation (boost more than 10 times) resulted in decrease of antigen specific IFN-γ and IL-2 production, reduction of memory CD8+ T cells, over-expression of immune checkpoint programmed cell death protein 1 (PD-1), and impaired the protective immunity against bacterial challenge. Treating the T cell functionally exhausted mice with IL-2 restored antigen-specific T cell responses and protective efficacy. In conclusion, persistent stimulation with M. tuberculosis antigens induced T cell dysfunction, which could be restored by complement of IL-2.
Highlights
Tuberculosis (TB) is a typical chronic infectious disease caused by Mycobacterium tuberculosis, which activates protective cell-mediated immune responses [1]
We found that following persistent M. tuberculosis antigen stimulation, T cells got functionally exhausted, while complementing interleukin 2 (IL-2) could restore dysfunction and reinvigorate immunity
The C57BL/6 mice were primed with Bacillus Calmette-Guérin (BCG) once and boosted with M. tuberculosis antigens MH plus LT70 or MH plus ESAT6 and CFP10 repeatedly for more than 10 weeks
Summary
Tuberculosis (TB) is a typical chronic infectious disease caused by Mycobacterium tuberculosis, which activates protective cell-mediated immune responses [1]. The protective immunity declines at late stage of TB, and the TB patients would die of consumption eventually. The number of Th1-type CD4+ T cells declined in TB patients [2]. CD4+ and CD8+ T cells were found. IL-2 Restores T-Cell Dysfunction functionally exhausted in mice infected with M. tuberculosis [3]. We and other groups observed that T cells experienced dysfunction/exhaustion in severe miliary sputum positive cavitary tuberculosis and MDR-TB [4, 5]. We suppose that T cells get functionally exhausted in sputum positive cavitary tuberculosis due to persistent stimulation by a large of bacteria proliferating in necrotic liquefied material inside cavitary lesions. We set up a mouse model to investigate our prediction
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
