Characterizing Early T Cell Responses in Nonhuman Primate Model of Tuberculosis

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.

Mucosal and systemic antigen-specific antibody responses correlate with protection against active tuberculosis in nonhuman primates

“…We saw tremendous heterogeneity in antibody responses among the CMs, irrespective of LTBI or TB group, consistent with other NHP and human studies profiling antibody responses to large numbers of Mtb proteins. 32 , 47 , 79 In both NHPs and humans, this heterologous immunity to Mtb is likely due to a combination of the large numbers of differentially expressed Mtb antigens, 42 , 80 differences in granuloma formation and immune activation, 37 , 41 prior BCG vaccination and/or exposure to environmental mycobacteria. 81 The resulting antibody heterogeneity contributes to the challenges of identifying immunodominant protective antigens.…”

Spontaneous Control of SIV Replication Does Not Prevent T Cell Dysregulation and Bacterial Dissemination in Animals Co-Infected with M. tuberculosis

“…We also examined how the extent of SIV replication affected CD4 + and CD8 + T cell frequencies in lung granulomas. Due to limited available cells from granulomas, the difficulties disaggregating cells from these tissues, and the number of unique antibodies we could include in each flow cytometry panel, we chose to focus on the frequencies of CD4 + and CD8 + T cells producing IFNγ and TNF-α, which are cytokines commonly associated with host defense against TB ( 31 , 39 – 42 ). By separating the SIV+ animals into viral controllers and viral non-controllers, we have now characterized (i) whether SIV and Mtb influence their corresponding pathogenesis and (ii) whether the extent of SIV replication impacts the frequency of functional CD4 + or CD8 + T cells in the tissues with TB disease.…”

Inhibition of indoleamine dioxygenase leads to better control of tuberculosis adjunctive to chemotherapy

“…High-parameter flow cytometry was performed on BAL cells and PBMCs at preinfection, at pretreatment, during treatment, at posttreatment, and at necropsy as previously described ( 17 , 34 , 66 , 74 , 77 ). The single cells prepared from lung, BAL, PBMCs, and other tissues were stained with surface and intracellular markers to study T cell phenotypes.…”