RT Journal Article SR Electronic T1 PD-1 blockade exacerbates Mycobacterium tuberculosis infection in rhesus macaques JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.08.05.237883 DO 10.1101/2020.08.05.237883 A1 Keith D Kauffman A1 Shunsuke Sakai A1 Nickiana E Lora A1 Sivaranjani Namasivayam A1 Paul J Baker A1 Olena Kamenyeva A1 Taylor W Foreman A1 Christine E Nelson A1 Deivide Oliveira-de-Souza A1 Caian L. Vinhaes A1 Ziv Yaniv A1 Cecilia S Lindestam Arleham A1 Alessandro Sette A1 Gordon J Freeman A1 Rashida Moore A1 the NIAID/DIR Tuberculosis Imaging Program A1 Alan Sher A1 Katrin D Mayer-Barber A1 Bruno B Andrade A1 Juraj Kabat A1 Laura E Via A1 Daniel L Barber YR 2020 UL http://biorxiv.org/content/early/2020/08/05/2020.08.05.237883.abstract AB 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.Competing Interest StatementDLB has patents on the PD-1/PD-1 pathway. GJF has patents/pending royalties on the PD-1/PD-L1 pathway from Roche, Merck MSD, Bristol-Myers-Squibb, Merck KGA, Boehringer-Ingelheim, AstraZeneca, Dako, Leica, Mayo Clinic, and Novartis. GJF has served on advisory boards for Roche, Bristol-Myers-Squibb, Xios, Origimed, Triursus, iTeos, NextPoint, IgM, Jubilant and GV20. GJF has equity in Nextpoint, Triursus, Xios, iTeos, IgM, and GV20.