Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.05.237883v1?rss=1 Authors: Kauffman, K. D., Sakai, S., Lora, N. E., Namasivayam, S., Baker, P. J., Kamenyeva, O., Foreman, T. W., Nelson, C. E., Oliveira-de-Souza, D., Vinhaes, C. L., Yaniv, Z., Lindestam Arleham, C. S., Sette, A., Freeman, G. J., Moore, R., the NIAID/DIR Tuberculosis Imaging Program,, Sher, A., Mayer-Barber, K. D., Andrade, B. B., Kabat, J., Via, L. E., Barber, D. L. 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 PD-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 PD-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 PD-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. Copy rights belong to original authors. Visit the link for more info