Latency-associated protein Acr1 impairs dendritic cell maturation and functionality: a possible mechanism of immune evasion by Mycobacterium tuberculosis.
Mycobacterium tuberculosis (M. tuberculosis) in latently infected individuals survives and thwarts the attempts of eradication by the immune system. During latency, Acr1 is predominantly expressed by the bacterium. However, whether M. tuberculosis exploits its Acr1 in impairing the host immunity remains widely unexplored. Hence, currently we have investigated the role of Acr1 in influencing the differentiation and function of dendritic cells (DCs), which play a cardinal role in innate and adaptive immunity. Therefore, for the first time, we have revealed a novel mechanism of mycobacterial Acr1 in inhibiting the maturation and differentiation of DCs by inducing tolerogenic phenotype by modulating the expression of PD-L1; Tim-3; indoleamine 2, 3-dioxygenase (IDO); and interleukin 10. Furthermore, Acr1 interferes in the differentiation of DCs by targeting STAT-6 and STAT-3 pathways. Continuous activation of STAT-3 inhibited the translocation of NF-κB in Acr1-treated DCs. Furthermore, Acr1 also augmented the induction of regulatory T cells. These DCs displayed decline in their antigen uptake capacity and reduced ability to help T cells. Interestingly, M. tuberculosis exhibited better survival in Acr1-treated DCs. Thus, this study provides a crucial insight into a strategy adopted by M. tuberculosis to survive in the host by impairing the function of DCs.
Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR), Chandigarh, India.
Kaneez F
KF
Siddiqui
Mohammed
M
Amir
Rama Krishna
RK
Gurram
Nargis
N
Khan
Ashish
A
Arora
Kammara
K
Rajagopal
Javed N
JN
Agrewala
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000276:immunology; D057131:Immune Evasion; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010641:Phenotype; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology; D038201:alpha-Crystallins / Q000276:immunology* / Q000494:pharmacology
D000942:Antigens, Bacterial; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; C494087:Stat3 protein, mouse; C494100:Stat6 protein, mouse; D038201:alpha-Crystallins
Acr1: alpha crystallin antigen; Mycobacterium tuberculosis; dendritic cells; immunosuppression