4‐1BB Expression and Signaling Regulates MAIT Cell Activation and Effector Functions

ABSTRACT

Mucosal associated invariant T (MAIT) cells are abundant unconventional T cells that recognize microbe‐derived riboflavin metabolites presented by MR1. Upon recognition, they become activated, produce proinflammatory cytokines, chemokines, and cytotoxic molecules. MAIT cells are also activated by cytokines independently of T cell receptor (TCR) engagement; however, these two signals can also act in concert to fine‐tune MAIT cell functions. Additionally, multiple other co‐stimulatory signals have also been reported that can boost MAIT cell effector responses to TCR or cytokine stimulation. However, a comprehensive study exploring the role of surface‐bound TNF receptor superfamily (TNFRSF) molecule 4‐1BB, well known for its co‐stimulatory function during conventional T cell activation, is lacking in the context of MAIT cells. In this study, we show that 4‐1BB is the earliest and most highly expressed TNFRSF co‐stimulatory molecule on MAIT cells upon activation by Escherichia coli , with expression seen as early as 6 h where it was predominantly MR1 mediated. 4‐1BB expression on MAIT cells following late activation was due to both TCR signaling and cytokine signaling. We found marked differences in MAIT cell activation and cytokine expression between 4‐1BB+ and 4‐1BB‐ MAIT cells suggesting 4‐1BB expression on MAIT cells is associated with functional superiority. By blocking 4‐1BB signaling or coculturing with a 4‐1BBL overexpressing cell line, we demonstrated an important role of co‐stimulation via 4‐1BB in MAIT cells during activation. Expression and signaling via 4‐1BB also enhanced T‐bet and Blimp1 expression. In summary, our study confirms a role for 4‐1BB signaling during MAIT cell activation.