Herpes simplex virus type 1 impairs mucosal-associated invariant T cells

Herpes simplex virus type 1 (HSV-1) is a highly successful pathogen that infects mucosal sites and adopts an arsenal of strategies to manipulate host immunity. Mucosal-associated invariant T (MAIT) cells are abundant innate-like T lymphocytes that recognize bacterial and fungal-derived vitamin B-related metabolites presented by major histocompatibility complex class I-related protein 1 (MR1). MAIT cells can also be activated in an MR1-independent manner via cytokine stimulation, predominantly by IL-12 and IL-18. MAIT cell alterations have been identified as being associated with a number of viral infections, but direct interactions between viruses and MAIT cells are poorly understood. It is unknown whether HSV-1 can infect MAIT cells and modulate their functions. Here, we show that HSV-1 can infect primary human MAIT cells, including CD4^±/CD8^± and CD56^± MAIT cell subpopulations. Furthermore, HSV-1 infection profoundly inhibits the functional capacity of MAIT cells to respond to T cell receptor (TCR)-dependent stimulation by the MAIT cell activating ligand 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) and to cytokine stimulation by IL-12/IL-18. HSV-1-infected MAIT cells display reduced cytotoxic potential, diminished synthesis of effector cytokines, and decreased expression of key cytokine receptors including IL-18R. In addition, MAIT cells exposed to HSV-1-infected fibroblasts but which remained uninfected (viral GFP-negative) also exhibit a suppressed effector response to TCR-dependent stimulation. The functional suppression of HSV-1-exposed MAIT cells was not mediated by a soluble factor within the supernatant, suggesting direct contact of MAIT cells with HSV-1-infected fibroblasts is required. Overall, this study reveals that HSV-1 can infect MAIT cells and substantially impair MAIT cell effector functions.