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

Abstract

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.

Importance: Mucosal-associated invariant T cells (MAIT cells) are "unconventional" immune cells that are becoming increasingly appreciated to play important roles in a variety of viral infections. Herpes simplex virus (HSV) causes significant human disease and is a master manipulator of multiple immune functions, but how this virus may control MAIT cells is poorly understood. We discovered that HSV can infect human MAIT cells and impair their functional capacity and also show that MAIT cells exposed to HSV, but which do not show evidence of infection, are similarly impaired. This study therefore identifies an additional immunomodulatory function of HSV.