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.
Highlights
Tuberculosis (TB) remains the leading cause of human death from a single infectious agent with a total of 1.4 million deaths in 2019 [1]
The macaques exposed to a low-dose controlled Mycobacterium tuberculosis (Mtb) infection were associated with an early IFN-g and tumor necrosis factor alpha (TNF-a) response in Mtb-specific CD4+ T cells
In the study by Harari et al [22], significant increase in the proportions of Mtbspecific CD4+T cells expressing TNF-a was seen in patients with active disease and proposed to be the strongest predictor of diagnosis of active disease
Summary
Tuberculosis (TB) remains the leading cause of human death from a single infectious agent with a total of 1.4 million deaths in 2019 [1]. The percentage of the infected population developing the clinical symptoms of TB remains small with a much higher percentage being able to control the naturally acquired infections [2, 3]. Generation of robust T cell responses is critical in the immunity to TB and are responsible for a dynamic balance between the host and pathogen in a latent TB infection (LTBI) [5]. While comorbidities, such as, with HIV is a known factor for the reactivation of LTBI [6], the underlying causes for the susceptibility to the active disease remains unknown. Stimulation with Mtb antigens Early Secretory Antigenic Target (ESAT)-6 and Culture Filtrate Protein (CFP)-10 induces IFN-g and TNF-a production by the CD4+ and CD8+T cells that may provide tools to study the role of these early responses in protection from a fatal infection
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