Modulation of pulmonary IL-21 expression during latent TB and Mtb/SIV co-infection

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Abstract

TB (Tuberculosis) and HIV co-infection remains a major global health challenge, with limited understanding of how these pathogens impact local immune responses in the lungs. This study is the first to investigate the modulation of IL-21 during LTBI and Mycobacterium tuberculosis (Mtb)/ Simian Immunodeficiency Virus (SIV) co-infection in non-human primates (NHP). We show that IL-21 expression, predominantly derived from CD4⁺ T cells, is significantly reduced in lungs of Mtb/SIV co-infected 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 Mtb-specific IFN-γ responses in co-infected animals. Together, our findings indicate that IL-21-producing CD4⁺ T cells are selectively and persistently impaired in the lungs during Mtb/SIV co-infection 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.

Authors

Vinay Shivanna, Renee D. Escalona, Colin Chuba, Shashi Prakash Singh, Ahmed A. Moustafa, J. Quincy Brown, Chenyao Xiao, Sangkyu Kim, Edward J. Dick Jr., Smriti Mehra, Mirko Paiardini, Riti Sharan