PREreview del CD4⁺ T cells promote fibrosis during metabolic dysfunction-associated steatohepatitis

Summary 

This preprint features an interesting and thoroughly conducted study on the role of CD4 + T cells in the pathogenesis of steatohepatitis as a consequence of metabolic dysfunction (MASH). The authors showed that CD4+ T-cell activation drives liver inflammation and fibrosis, and that OX40L therapeutic targeting reduces disease phenotypes using a potent combination of methods, including CyTOF, CITE-seq, genetic CD4 deletion, OX40L antibody blockage of the OX40L OX40 axis, and human precision-cut liver sections. The multi-modal design and the presence of human tissue give this work good translational relevance and thus makes this a valuable resource to the field.

Major strengths

• Technical rigor and breadth: single-cell proteomics, transcriptomics, functional mouse models, and human PCLS integrate to form a powerful, cross-validated dataset.

•  Clinical relevance: OX40L inhibition reverses fibrosis in pre-existing disease and lowers the levels of inflammatory signals in human liver slices, which puts OX40 as a practical therapeutic target.

• Resource value; The CITE-seq atlas of hepatic CD4+ T cells is a valuable addition to the mechanistic studies in future.

Suggestions

• Open reporting - Have the number of biological replicates of all mouse experiments and human donors clearly indicated and summarized in a table or extended methods section.

• Antibody description - Include dose, clone, route, supplier and validation information about the OX40L-blocking antibody in order to have reproducibility.

• Mechanistic insight – Although there is evidence to indicate that a CD4→macrophage→fibrosis pathway is possible, further evidence (such as co-culture or cytokine-neutralization experiments) would support causality.

• Human data - The data to support the PCLS results indicate the characteristics of the donor, slice viability, and protein/cytotokine results.

Overall assessment

This is a quality study that greatly contributes to the current body of knowledge on immune drivers in MASH and presents an effective treatment option. It will be more appropriate to be published in a formal journal with a few minor amendments, and it will be of high interest to researchers in the hepatology and immunology fields.

Competing interests

The author declares that they have no competing interests.