bims-maitce 2024-11-03 papers

Issue of 2024–11–03
two papers selected by
Andy E. Hogan, Maynooth University

Nat Commun. 2024 Oct 28. 15(1): 9287

Protective effect of TCR-mediated MAIT cell activation during experimental autoimmune encephalomyelitis.

Mark Walkenhorst, Jana K Sonner, Nina Meurs, Jan Broder Engler, Simone Bauer, Ingo Winschel, Marcel S Woo, Lukas Raich, Iris Winkler, Vanessa Vieira, Lisa Unger, Gabriela Salinas, Olivier Lantz, Manuel A Friese, Anne Willing.

Mucosal-associated invariant T (MAIT) cells express semi-invariant T cell receptors (TCR) for recognizing bacterial and yeast antigens derived from riboflavin metabolites presented on the non-polymorphic MHC class I-related protein 1 (MR1). Neuroinflammation in multiple sclerosis (MS) is likely initiated by autoreactive T cells and perpetuated by infiltration of additional immune cells, but the precise role of MAIT cells in MS pathogenesis remains unknown. Here, we use experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, and find an accumulation of MAIT cells in the inflamed central nervous system (CNS) enriched for MAIT17 (RORγt+) and MAIT1/17 (T-bet+RORγt+) subsets with inflammatory and protective features. Results from transcriptome profiling and Nur77GFP reporter mice show that these CNS MAIT cells are activated via cytokines and TCR. Blocking TCR activation with an anti-MR1 antibody exacerbates EAE, whereas enhancing TCR activation with the cognate antigen, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil, ameliorates EAE severity, potentially via the induction of amphiregulin (AREG). In summary, our findings suggest that TCR-mediated MAIT cell activation is protective in CNS inflammation, likely involving an induction of AREG.

DOI: https://doi.org/10.1038/s41467-024-53657-9

Nature. 2024 Oct 30.

Rhythmic IL-17 production by γδ T cells maintains adipose de novo lipogenesis.

Aaron Douglas, Brenneth Stevens, Miguel Rendas, Harry Kane, Evan Lynch, Britta Kunkemoeller, Karl Wessendorf-Rodriguez, Emily A Day, Caroline Sutton, Martin Brennan, Katie O'Brien, Ayano C Kohlgruber, Hannah Prendeville, Amanda E Garza, Luke A J O'Neill, Kingston H G Mills, Christian M Metallo, Henrique Veiga-Fernandes, Lydia Lynch.

The circadian rhythm of the immune system helps to protect against pathogens1-3; however, the role of circadian rhythms in immune homeostasis is less well understood. Innate T cells are tissue-resident lymphocytes with key roles in tissue homeostasis4-7. Here we use single-cell RNA sequencing, a molecular-clock reporter and genetic manipulations to show that innate IL-17-producing T cells-including γδ T cells, invariant natural killer T cells and mucosal-associated invariant T cells-are enriched for molecular-clock genes compared with their IFNγ-producing counterparts. We reveal that IL-17-producing γδ (γδ17) T cells, in particular, rely on the molecular clock to maintain adipose tissue homeostasis, and exhibit a robust circadian rhythm for RORγt and IL-17A across adipose depots, which peaks at night. In mice, loss of the molecular clock in the CD45 compartment (Bmal1∆Vav1) affects the production of IL-17 by adipose γδ17 T cells, but not cytokine production by αβ or IFNγ-producing γδ (γδIFNγ) T cells. Circadian IL-17 is essential for de novo lipogenesis in adipose tissue, and mice with an adipocyte-specific deficiency in IL-17 receptor C (IL-17RC) have defects in de novo lipogenesis. Whole-body metabolic analysis in vivo shows that Il17a-/-Il17f-/- mice (which lack expression of IL-17A and IL-17F) have defects in their circadian rhythm for de novo lipogenesis, which results in disruptions to their whole-body metabolic rhythm and core-body-temperature rhythm. This study identifies a crucial role for IL-17 in whole-body metabolic homeostasis and shows that de novo lipogenesis is a major target of IL-17.

DOI: https://doi.org/10.1038/s41586-024-08131-3