TY - UNPB
T1 - Multimodal memory T cell profiling identifies a reduction in a polyfunctional Th17 state associated with tuberculosis progression
AU - Nathan, Aparna
AU - Beynor, Jessica I
AU - Baglaenko, Yuriy
AU - Suliman, Sara
AU - Ishigaki, Kazuyoshi
AU - Asgari, Samira
AU - Huang, Chuan-Chin
AU - Luo, Yang
AU - Zhang, Zibiao
AU - Tamara, Kattya Lopez
AU - Jimenez, Judith
AU - Calderon, Roger I
AU - Lecca, Leonid
AU - Rhijn, Ildiko van
AU - Moody, Branch
AU - Murray, Megan B
AU - Raychaudhuri, Soumya
PY - 2020/4/25
Y1 - 2020/4/25
N2 - Mycobacterium tuberculosis (M.tb) results in 10 million active tuberculosis (TB) cases and 1.5 million deaths each year, making it the world's leading infectious cause of death. Infection leads to either an asymptomatic latent state or TB disease. Memory T cells have been implicated in TB disease progression, but the specific cell states involved have not yet been delineated because of the limited scope of traditional profiling strategies. Furthermore, immune activation during infection confounds underlying differences in T cell state distributions that influence risk of progression. Here, we used a multimodal single-cell approach to integrate measurements of transcripts and 30 functionally relevant surface proteins to comprehensively define the memory T cell landscape at steady state (i.e., outside of active infection). We profiled 500,000 memory T cells from 259 Peruvians > 4.7 years after they had either latent M.tb infection or active disease and defined 31 distinct memory T cell states, including a CD4+CD26+CD161+CCR6+ effector memory state that was significantly reduced in patients who had developed active TB (OR = 0.80, 95% CI: 0.73-0.87, p = 1.21 x 10-6). This state was also polyfunctional; in ex vivo stimulation, it was enriched for IL-17 and IL-22 production, consistent with a Th17-skewed phenotype, but also had more capacity to produce IFNgamma than other CD161+CCR6+ Th17 cells. Additionally, in progressors, IL-17 and IL-22 production in this cell state was significantly lower than in non-progressors. Reduced abundance and function of this state may be an important factor in failure to control M.tb infection.
### Competing Interest Statement
The authors have declared no competing interest.
AB - Mycobacterium tuberculosis (M.tb) results in 10 million active tuberculosis (TB) cases and 1.5 million deaths each year, making it the world's leading infectious cause of death. Infection leads to either an asymptomatic latent state or TB disease. Memory T cells have been implicated in TB disease progression, but the specific cell states involved have not yet been delineated because of the limited scope of traditional profiling strategies. Furthermore, immune activation during infection confounds underlying differences in T cell state distributions that influence risk of progression. Here, we used a multimodal single-cell approach to integrate measurements of transcripts and 30 functionally relevant surface proteins to comprehensively define the memory T cell landscape at steady state (i.e., outside of active infection). We profiled 500,000 memory T cells from 259 Peruvians > 4.7 years after they had either latent M.tb infection or active disease and defined 31 distinct memory T cell states, including a CD4+CD26+CD161+CCR6+ effector memory state that was significantly reduced in patients who had developed active TB (OR = 0.80, 95% CI: 0.73-0.87, p = 1.21 x 10-6). This state was also polyfunctional; in ex vivo stimulation, it was enriched for IL-17 and IL-22 production, consistent with a Th17-skewed phenotype, but also had more capacity to produce IFNgamma than other CD161+CCR6+ Th17 cells. Additionally, in progressors, IL-17 and IL-22 production in this cell state was significantly lower than in non-progressors. Reduced abundance and function of this state may be an important factor in failure to control M.tb infection.
### Competing Interest Statement
The authors have declared no competing interest.
UR - https://www.mendeley.com/catalogue/2de9856d-8907-3b7d-9303-80acedf83d60/
U2 - 10.1101/2020.04.23.057828
DO - 10.1101/2020.04.23.057828
M3 - Preprint
BT - Multimodal memory T cell profiling identifies a reduction in a polyfunctional Th17 state associated with tuberculosis progression
PB - bioRxiv
ER -