IL-15 Superagonist N-803 Enhances IFN-gamma Production of MAIT Cells in SIV+ Macaques

Mucosal associated invariant T (MAIT) cells are innate T cells that recognize bacterial metabolites and secrete cytokines and cytolytic enzymes to destroy infected target cells. This makes MAIT cells promising targets for immunotherapy to combat bacterial infections. Here, we analyzed the effects of an immunotherapeutic agent, the IL-15 superagonist N-803, on MAIT cell activation, trafficking, and cytolytic function in macaques. We found that N-803 could activate MAIT cells in vitro and increase their ability to produce IFN-gamma in response to bacterial stimulation. To expand upon this, we examined the phenotypes and functions of MAIT cells present in samples collected from PBMC, airways (bronchoalveolar lavage [BAL] fluid), and lymph nodes (LN) from rhesus macaques that were treated in vivo with N-803. N-803 treatment led to a transient 6 to 7-fold decrease in the total number of MAIT cells in the peripheral blood, relative to pre N-803 time points. Concurrent with the decrease in cells in the peripheral blood, we observed a rapid decline in the frequency of CXCR3(+)CCR6(+) MAITs. This corresponded with an increase in the frequency of CCR6(+) MAITs in the BAL fluid, and higher frequencies of ki-67(+) and granzyme B+ MAITs in the blood, LN, and BAL fluid. Finally, N-803 improved the ability of MAIT cells collected from PBMC and airways to produce IFN-gamma in response to bacterial stimulation. Overall, N-803 shows the potential to transiently alter the phenotypes and functions of MAIT cells, which could be combined with other strategies to combat bacterial infections.