Mucosal-associated invariant T (MAIT) cells represent a unique subset of immune cells that bridge the gap between the innate and adaptive immune systems. Unlike conventional T cells, which typically recognize fragments of proteins, MAIT cells respond to a distinct class of molecules. Their presence throughout the body, particularly at sites exposed to microbes, highlights their importance in rapid defense against various threats.
What Are MAIT Cells?
MAIT cells are unconventional T lymphocytes. A defining characteristic is their semi-invariant T cell receptor (TCR), expressing a limited set of TCR alpha chains, predominantly TRAV1-2 in humans. This limited diversity contrasts with the vast repertoire of TCRs on conventional T cells, which recognize an almost infinite array of peptide antigens.
MAIT cells are abundant in humans, making up a significant portion of T cells in the blood, liver, lungs, and mucosal tissues like the gut. Their presence in these barrier tissues suggests a role in interacting with the external environment. Unlike conventional T cells restricted by variable Major Histocompatibility Complex (MHC) molecules, MAIT cells recognize antigens presented by the highly conserved, non-polymorphic MHC-related protein 1 (MR1).
MAIT cells express surface markers like high levels of CD161 and the interleukin-18 receptor. They often display an “effector-memory” phenotype, poised for a rapid response. This innate-like quality allows them to react quickly to infections without needing prior extensive activation or clonal expansion, a hallmark of conventional adaptive immune responses.
How MAIT Cells Detect Threats
MAIT cells detect threats by recognizing specific microbial metabolites presented by the MR1 molecule. Unlike conventional T cells, MAIT cells are activated by small-molecule byproducts of microbial metabolism. These antigens are primarily biosynthetic derivatives of the riboflavin (vitamin B2) synthesis pathway, produced by many bacteria and yeasts.
The MR1 molecule plays a specialized role in presenting these non-peptide antigens. When microbial riboflavin metabolites are present, they bind to MR1 within the endoplasmic reticulum (ER) of cells. This binding causes MR1 to fold and move to the cell surface for presentation to MAIT cells.
This unique activation pathway enables MAIT cells to respond rapidly to a wide range of bacterial and fungal infections. Since the riboflavin synthesis pathway is highly conserved across many microbial species but absent in humans, MAIT cells serve as a broad-spectrum sensor for microbial presence. While primarily activated by MR1-bound microbial metabolites, MAIT cells can also be activated in a TCR-independent manner by inflammatory cytokines like interleukin-12 (IL-12) and interleukin-18 (IL-18), particularly during viral infections.
Roles in Health and Disease
MAIT cells play multifaceted roles in health and disease. In infectious diseases, they act as rapid responders to bacterial and fungal pathogens. Upon activation, MAIT cells secrete pro-inflammatory cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), crucial for clearing infections. They also possess cytotoxic capabilities, directly killing infected cells through molecules like granzyme and perforin. MAIT cells contribute to immunity against infections like tuberculosis and bacterial pneumonia.
Beyond direct pathogen clearance, MAIT cells are involved in broader inflammatory processes and have complex roles in autoimmune diseases. In some autoimmune diseases like multiple sclerosis, systemic lupus erythematosus, and inflammatory bowel diseases, circulating MAIT cell numbers can be reduced, or remaining cells may show increased cytokine production. Their exact contribution can be protective or harmful depending on the specific context.
Emerging research also points to MAIT cell involvement in cancer, where their role is still being investigated. They can exhibit anti-tumor activity by releasing cytotoxic molecules and IFN-γ, which helps activate other immune cells involved in tumor surveillance. However, MAIT cells within the tumor microenvironment can also produce pro-inflammatory cytokines like IL-17 and IL-13, which may contribute to tumor growth and progression in some cancers.
MAIT cells also contribute to tissue homeostasis, particularly in mucosal tissues like the gut. They help maintain the health of these barrier sites, responding to both commensal (beneficial) bacteria and invading pathogens.