The TL1A-DR3 Axis Selectively Drives Effector Functions in Human MAIT Cells

J Immunol. 2019 Dec 1;203(11):2970-2978. doi: 10.4049/jimmunol.1900465. Epub 2019 Oct 18.


Mucosal-associated invariant T (MAIT) cells are semi-invariant T cells specifically recognizing riboflavin derivatives that are synthesized by many bacteria and fungi presented by MHC class I-related MR1 molecules. Accumulating evidence, however, indicates that MAIT cell functions are inducible by cytokine stimuli in the absence of TCR ligation, identifying MAIT cells as innate sentinels in inflammatory environments. In this study, we demonstrate that death receptor 3 (DR3), a member of the TNFR superfamily, is ex vivo expressed and predominantly upregulated on the surface of human MAIT cells by innate cytokine stimulation. In turn, the DR3 ligand TNF-like protein 1A (TL1A) licenses innate TNF-α production in the absence of cognate triggers, being sufficient to promote activation of primary endothelial cells in vitro. TL1A further amplifies synthesis of IFN-γ and granzyme B in the presence of otherwise weak innate stimuli and strongly augments polyfunctionality. Mechanistically, TL1A potentiates T-bet expression, early NF-κB, and late p38 MAP kinase phosphorylation, with the latter being indispensable for TNF-α production by MAIT cells. Of note, endogenous TL1A is also rapidly released from PBMC cultures in response to bacterial triggering, thereby equally augmenting Ag-specific MAIT cell effector functions. In summary, to our knowledge, we identify a new inflammatory mechanism in MAIT cells linking the DR3/TL1A axis with amplification of TCR-dependent and -independent effector functions, particularly inducing excessive innate TNF-α production. Given that both TL1A and TNF-α are abundantly present at sites of chronic inflammation, the contribution of MAIT cells in such scenarios needs to be determined.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Inflammation / immunology
  • Mucosal-Associated Invariant T Cells / immunology*
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Tumor Necrosis Factor, Member 25 / immunology*
  • Tumor Necrosis Factor Ligand Superfamily Member 15 / immunology*


  • Receptors, Antigen, T-Cell
  • Receptors, Tumor Necrosis Factor, Member 25
  • TNFRSF25 protein, human
  • TNFSF15 protein, human
  • Tumor Necrosis Factor Ligand Superfamily Member 15