Characterizing Early T Cell Responses in Nonhuman Primate Model of Tuberculosis

• Type of Material: Article
• Authors: Riti Sharan, Texas Biomedical Research Institute; Dhiraj Kumar Singh, Texas Biomedical Research Institute; Jyothi Rengarajan, Emory University; Deepak Kaushal, Texas Biomedical Research Institute
• Language: English
• Date: 2021-08-17
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Sharan, Singh, Rengarajan and Kaushal
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fimmu.2021.706723
• Title of Journal or Parent Work: FRONTIERS IN IMMUNOLOGY
• Volume: 12
• Start Page: 706723
• End Page: 706723
• Grant/Funding Information: This work was primarily supported by NIH grants R01AI111943 and R01AI123047 (to DK and JR), 1 K01 OD031898-01 (to RS) with additional support from NIH grants R01AI111914, R01AI134240, R01AI138587, and U19AI111211 and institutional grants from the Office of the Director, NIH P51OD011133 (to SNPRC), P30 RR00165 and P51OD011132 (to YNPRC), and P30 AI050409 [Emory University Center for AIDS Research (CFAR)].
• Keywords: ESAT-6/CFP-10; INFECTION; IFN-gamma; SEVERITY; TNF-alpha; LYMPHOCYTES; REACTIVATION; IFN-GAMMA; Immunology; T cell responses; CD4(+); Science & Technology; PROTECTION; MECHANISMS; Life Sciences & Biomedicine; LATENT TUBERCULOSIS; CD8(+); LTBI
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading infectious disease killer worldwide with 1.4 million TB deaths in 2019. While the majority of infected population maintain an active control of the bacteria, a subset develops active disease leading to mortality. Effective T cell responses are critical to TB immunity with CD4+ and CD8+ T cells being key players of defense. These early cellular responses to TB infection have not yet been studied in-depth in either humans or preclinical animal models. Characterizing early T cell responses in a physiologically relevant preclinical model can provide valuable understanding of the factors that control disease development. We studied Mtb-specific T cell responses in the lung compartment of rhesus macaques infected with either a low- or a high-dose of Mtb CDC1551 via aerosol. Relative to baseline, significantly higher Mtb-specific CD4+IFN-γ+ and TNF-α+ T cell responses were observed in the BAL of low dose infected macaques as early as week 1 post TB infection. The IFN-γ and TNF-a response was delayed to week 3 post infection in Mtb-specific CD4+ and CD8+T cells in the high dose group. The manifestation of earlier T cell responses in the group exposed to the lower Mtb dose suggested a critical role of these cytokines in the antimycobacterial immune cascade, and specifically in the granuloma formation to contain the bacteria. However, a similar increase was not reflected in the CD4+ and CD8+IL-17+ T cells at week 1 post infection in the low dose group. This could be attributed to either a suppression of the IL-17 response or a lack of induction at this early stage of infection. On the contrary, there was a significantly higher IL-17+ response in Mtb-specific CD4+ and CD8+T cells at week 3 in the high dose group. The results clearly demonstrate an early differentiation in the immunity following low dose and high dose infection, largely represented by differences in the IFN-γ and TNF-α response by Mtb-specific T cells in the BAL. This early response to antigen expression by the bacteria could be critical for both bacterial growth control and bacterial containment.