Mucosal-associated invariant T (MAIT) cell contributions to mucosal immunity
Slichter, Chloe Knights
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Mucosal-associated invariant T (MAIT) cells are a semi-invariant T cell subset that are located in blood, liver and mucosal tissues. When activated MAIT cells display potent effector functions including secretion of secretion of pro-inflammatory cytokines such as interferon-γ (IFNγ) and tumor-necrosis factor alpha (TNFα) and lysis of bacterially-infected cells through granzyme B. MAIT cells recognize bacterial-derived metabolites, from commensal and pathogenic bacteria, via their semi-invariant T cell receptor (TCR) in the context of the MHC class I related molecule MR1. How MAIT cells distinguish between commensal and pathogenic bacteria is unknown. MAIT cell frequency and function is decreased in the blood in the chronic phase of HIV, HCV, and tuberculosis infection and during these infections MAIT cells express inhibitory receptors. Whether MAIT cells are activated during the acute stage of infection and how MAIT cell responses are turned off is unclear. Here, we address basic questions regarding MAIT cell activation and function during inflammatory disease states: 1) how MAIT cells distinguish between pathogenic and commensal antigen, 2) MAIT functional responses during acute viral infection and 3) how the MAIT cell response is turned off. We demonstrate that a TCR signal alone is not sufficient for sustained MAIT cell effector function, but rather a TCR + cytokine signal is necessary for MAIT cell activation. We propose that this unique control of effector function allows MAIT cells to respond to the same TCR signal (commensal or pathogen derived) in a dichotomous and situation-specific manner. Using an SIV model of infection, we demonstrate that MAIT cells at mucosal sites undergo rapid activation, and acquire effector functions such as expression of tumor-necrosis factor alpha (TNFα) and granzyme B. In contrast, MAIT cells in the periphery display an early loss of cytokines important for barrier immunity, such as IL-17 and IL-22. These data suggest that MAIT cells become activated early in the mucosa after infection and may play an important role in mucosal homeostasis. Lastly, we interrogate MAIT cell function and transcriptional profiles in inflamed mucosal tissue to address how the MAIT cell response is turned off. We find distinct patterns of inhibitory transcripts by MAIT cells within the inflamed mucosa, including high expression of the inhibitory receptor cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and that cytokine signals alone are sufficient for expression of CTLA-4. Together, our data highlight MAIT cells as important effector cells located at the site of pathogen entry, and begin to elucidate the mechanisms of MAIT cell regulation during inflammatory disease states.
- Pathobiology