The immune checkpoint TIGIT is upregulated on T cells during bacterial infection and is a potential target for immunotherapy

Antibiotic resistance is a major public health threat, and alternatives to antibiotic therapy are urgently needed. Immunotherapy, particularly the blockade of inhibitory immune checkpoints, is a leading treatment option in cancer and autoimmunity. In this study, we used a murine model of Salmonella Typhimurium infection to investigate whether immune checkpoint blockade could be applied to bacterial infection. We found that the immune checkpoint T-cell immunoglobulin and ITIM domain (TIGIT) was significantly upregulated on lymphocytes during infection, particularly on CD4+ T cells, drastically limiting their proinflammatory function. Blockade of TIGIT in vivo using monoclonal antibodies was able to enhance immunity and improve bacterial clearance. The efficacy of anti-TIGIT was dependent on the capacity of the antibody to bind to Fc (fragment crystallizable) receptors, giving important insights into the mechanism of anti-TIGIT therapy. This research suggests that targeting immune checkpoints, such as TIGIT, has the potential to enhance immune responses toward bacteria and restore antibacterial treatment options in the face of antibiotic resistance. In this experiment, we investigated the effect of TIGIT on CD4+ T cells by performing bulk RNA-sequencing on WT or TIGIT-/- CD4+ T cells in the context of S. Typhimurium infection. Four-week-old recipient CD45.1 mice were sublethally irradiated with two doses of 550 cGy 3 h apart. Four hours after the second dose of irradiation, mice were injected intravenously with a 50:50 mix of bone marrow cells from WT CD45.1.2 and Tigit−/− (CD45.2) mice. Mice were maintained on neomycin water for at least 3 weeks and used for experimentation 8–10 weeks after reconstitution. Mice were challenged with an attenuated aroA mutant strain of Salmonella enterica subspecies Typhimurium, SL3261, using a dose of 1e6 CFU in 200 μL by intraperitoneal injection. After 10 days, CD4+ T cells were sorted by flow cytometry and RNA was isolated using the Maxwell RSC simplyRNA Cells RNA Extraction Kit (Promega, Madison, WI, USA) as per the manufacturer's instructions. Libraries were prepped using an Illumina Stranded mRNA prep Kit (Illumina, San Diego, CA, USA) and sequenced on a NovaSeq6000 platform (single end, 100 bp).