PD-1 blockade exacerbatesMycobacterium tuberculosisinfection in rhesus macaques

Abstract

Boosting immune cell function by targeting the co-inhibitory receptor PD-1 may have applications in the treatment of chronic infections. Here we examine the role of PD-1 during Mycobacterium tuberculosis (Mtb) infection of rhesus macaques. Animals treated with αPD-1 mAb developed worse disease and higher granuloma bacterial loads compared to isotype control treated monkeys. PD-1 blockade increased the number and functionality of granuloma Mtb-specific CD8 T cells. In contrast, Mtb-specific CD4 T cells in αPD-1 treated macaques were not increased in number or function in granulomas, upregulated high levels of CTLA-4 and exhibited reduced intralesional trafficking in live imaging studies. In granulomas of αPD-1 treated animals, multiple pro-inflammatory cytokines were elevated, and more cytokines correlated with bacterial loads, leading to the identification of a role for caspase 1 in the exacerbation of tuberculosis after PD-1 blockade. Lastly, increased Mtb bacterial loads after PD-1 blockade were found to associate with the composition of the intestinal microbiota prior to infection in individual macaques. Therefore, PD-1-mediated co-inhibition is required for control of Mtb infection in macaques, perhaps due to its role in dampening detrimental inflammation as well as allowing for normal CD4 T cell responses.

Exaggerated IL-17A activity in human in vivo recall responses discriminates active tuberculosis from latent infection and cured disease

“…Evolutionary conservation of Mtb-targeting T cell epitopes strongly suggests that T cell responses promote immunopathology ( 49 ), and that their negative regulation is critical to preventing disease manifestation ( 50 ). Our data support the hypothesis that exaggerated IL-17A/F responses arise from Th17 cells, but they do not unequivocally exclude other cellular sources.…”

CD4 T cells are rapidly depleted from tuberculosis granulomas following acute SIV co-infection

“…To further characterize the impact of early SIV infection on the inflammatory milieu of granulomas, we next used network density analysis of Spearman correlations 24,25 to quantify the interconnectivity of these variables (Fig. 2c).…”

TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis

“…The microbiome produces a large proportion of succinate circulating in plasma (21), thus providing a potential avenue through which microbial composition could regulate the inflammatory response in TB disease. Indeed, microbiome differences in rhesus macaques have been associated with TB disease severity and bacterial burden (22). Another potential explanation that is not mutually exclusive is the ability of Mtb to induce aerobic glycolysis (23, 24).…”

“…The decline in plasma concentrations of TCA cycle intermediates was mirrored by declines in plasma concentrations of IL-1b, which also significantly declined after 1 year of MDR-TB treatment (Figure 8E). (22). Another potential explanation that is not mutually exclusive is the ability of Mtb to induce aerobic glycolysis (23,24).…”