T cells are essential for immune surveillance since they recognize, attack and remove virus-infected and cancer-transformed cells. Inhibitory receptors (IR) temper inflammatory responses to microbial infections by regulating T cell effector activity. In humans, persistent viruses such as HIV, HCV and HBV as well as several types of cancer have adapted to exploit IR signaling by upregulating IR ligands, resulting in the suppression of T cell function (exhaustion) and escape from immune control. T cell exhaustion and the resurrection of T cell function, by neutralizing IR signaling, was first delineated in C57BL/6 mice following infection with the Clone 13 variant of lymphocytic choriomeningitis virus (LCMV). Infection with Clone 13 results in suboptimal CD4 and CD8 T cell effector function, ranging from reduced to absent cytotoxic capacity of CD8 T cells to decreased production of anti-viral cytokines such as IFN-? and TNF-?. Chronicling the resurrection of anti-viral T cell activity using antibodies that target IRs suggests that an in vitro phenotypic assay using the LCMV system could be an effective screening platform to identify novel small pharmacologic and beneficial molecule(s) that disrupt pathways regulating T cell dysfunction. To this end, we developed a screening strategy that utilizes transgenic mice (IFN-?-YFP) combined with high-throughput (HTS) flow cytometry to examine compounds that potentiate IFN-? expression in exhausted T cells isolated from LCMV infected animals. Using this approach, we propose to screen a best-in-class drug repurposing collection of 12,000 compounds (ReFrame) developed by TSRI?s non-profit affiliate, Calibr. The ReFrame library?s scale and comprehensiveness will allow us to explore complex biological processes in T cells and identify novel therapeutic agents that can reverse T cell exhaustion in the context of persistent viral infections and cancer.

Public Health Relevance

T cells are an essential component of the immune system that target and remove virus infected and cancer transformed cells. Inhibitory receptors temper T cell responses to microbial infections by regulating T cell effector activity and promote the loss of T cell function (exhaustion). We developed a robust screening strategy to explore complex biological processes in T cells and identify novel therapeutic agents that can restore T cell function in the context of persistent viral infections and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI141842-02
Application #
9823854
Study Section
Immunity and Host Defense (IHD)
Program Officer
Davis, Mindy I
Project Start
2018-11-15
Project End
2020-10-31
Budget Start
2019-11-01
Budget End
2020-10-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037