Modulation of pulmonary IL-21 expression during latent TB and M. tuberculosis/SIV coinfection.

Tuberculosis (TB) and HIV coinfection remains a major global health challenge, with limited understanding of how these pathogens affect local immune responses in the lungs. This study is the first to our knowledge to investigate the modulation of IL-21 during LTBI and M. tuberculosis/SIV coinfection in nonhuman primates (NHP). We show that IL-21 expression, predominantly derived from CD4+ T cells, is significantly reduced in lungs of M. tuberculosis/SIV coinfected macaques, especially in the absence of cART. Although cART and cART with 3HP partially restore IL-21-producing CD4+ T cells, levels remain below those in LTBI, indicating ongoing immune impairment. Spatial transcriptomic analysis suggests localized alterations in immune signaling, including differences in STAT1- and STAT3-associated transcriptional profiles and reduced M. tuberculosis-specific IFN-γ responses in coinfected animals. Together, our findings indicate that IL-21-producing CD4+ T cells are selectively and persistently impaired in the lungs during M. tuberculosis/SIV coinfection, despite antimicrobial and antiviral therapy. These results highlight a compartment-specific deficit in immune reconstitution and suggest that IL-21-associated pathways may warrant further investigation as potential targets for host-directed therapeutic strategies.