Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• Mucosal-associated invariant T (MAIT) cells

• Iron metabolism

• Immunometabolism

Main Findings

MAIT cells are a unique population of innate-like lymphocytes that contain an invariant T cell receptor (TCR) alpha chain. First described as a cell population enriched in mucosal tissues, they serve as an important first line of defence against infections at mucosal surfaces but may also contribute to some inflammatory and autoimmune diseases. The Hogan lab and others have described some metabolic dependencies in activated MAIT cells including cMyc-mTORC1-mediated glycolysis and amino acid flux via SLC7A5. Conventional effector T cells also rely on iron flux during activation to drive their proliferation and effector functions, but it is not known whether MAIT cells also require iron during activation.

In this preprint, Eimar Ryan et al tested whether MAIT cells require iron. In all experiments, MAIT cells were isolated from peripheral blood of healthy human donors. Upon activation with TCR stimulation and IL-18, MAIT cells increased both CD71 (transferrin receptor) expression and iron (ferritin) uptake. Restricting iron via chelation with DFO limited ATP production in MAIT cells, and shifted their metabolic dependency to less fatty acid oxidation and more glycolysis. Limiting iron also restricted MAIT cell functions such as proliferation, and production of IL-17 and IFNg.

Limitations

• The limitations of the study are the source of MAIT cells from peripheral blood. Although the use of primary human cells is a strength in a translational sense, testing MAIT cells from other body sites such as mucosal tissues would be an important next step. Furthermore, the isolation of these MAIT cells did not differentiate between subsets such as MAIT1 and MAIT17s, which may have different metabolic programs and/or dependencies on iron. A recent publication offers a new strategy to sort these MAIT cell populations from peripheral blood using cell surface markers (PMID:37231163). Differentiating between these two cell populations may offer more clarity in metabolic phenotypes.

• MAIT cells can be activated by TCR stimulation, or cytokines (IL-18) alone. Therefore, it should be tested whether these findings are applicable to both of those stimuli or is conserved with any type of MAIT cell activation.

• Some smaller improvements that could be made to the presentation of the data include: showing the percentages of cells that produce cytokines, presenting CellTraceViolet data with respect to undivided cell peak vs. divided cells, and to show a representative basal signal or unstimulated cell signal for Figure 3c.

Significance/Novelty

The findings of this preprint are relevant to the fields of immunometabolism, MAIT cell biology, and mucosal immunology. Although it is expected that MAIT cells would require iron for proliferation, it is important to test how iron restriction could impact their function.

Iron deficiency is the most prevalent nutritional deficit on a global scale. Therefore, these findings are especially important to understand how malnutrition and/or iron deficiency could be impacting MAIT cell function in humans.

Credit

Reviewed by Kelsey Voss, Nikolina Bradaric and Donald Okoye as part of a cross-institutional journal club between the Vanderbilt University Medical Center (VUMC), the Max-Delbrück Center Berlin, the Medical University of Vienna and other life science institutes in Vienna.

The authors declare no conflict of interests in relation to their involvement in the review.