SLAM/SAP signaling regulates discrete γδ T cell developmental checkpoints and shapes the innate-like γδ TCR repertoire

  1. Department of Surgery, Larner College of Medicine, University of Vermont, Burlington, Vermont 05405, USA
  2. Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont Medical Center, Burlington, Vermont 05405, USA

Peer review process

Not revised: This Reviewed Preprint includes the authors’ original preprint (without revision), an eLife assessment, public reviews, and a response from the authors (if available).

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Editors

  • Reviewing Editor
    Shiny Nair
    Yale University, New Haven, United States of America
  • Senior Editor
    Satyajit Rath
    Indian Institute of Science Education and Research (IISER), Pune, India

Reviewer #1 (Public Review):

Summary:

In this study, the authors advance their previous findings on the role of the SLAM-SAP signaling pathway in the development and function of multiple innate-like gamma-delta T-cell subsets. Using a high throughput single-cell proteogenomics approach, the authors uncover SAP-dependent developmental checkpoints, and the role of SAP signaling in regulating the diversion of γδ T cells into the αβ T cell developmental pathway. Finally, the authors define TRGV4/TRAV13-4(DV7)-expressing T cells as a novel, SAP-dependent Vγ4 γδT1 subset.

Strengths:

This study furthers our understanding of the importance and complexity of the SLAM-SAP signaling pathway not only in the development of innate-like γδ T cells but also in how it potentially balances the γδ/αβ T cell lineage commitment. Additionally, this study reveals the role of SAP-dependent events in the generation of γδ TCR repertoire.

The conclusions of the study are supported by well-thought-out experiments and compelling data.

Weaknesses:

No major weaknesses in the study were identified.

Reviewer #2 (Public Review):

Summary:

Mistri et al explore the role of SLAM-SAP signaling in the developmental programming of innate-like gd T cell subsets. Using proteo-genomics, they determined that abrogation of SLAM-SAP signaling altered that programming, reducing some IL-17-producing subsets, including a novel Vγ4 γδT1 subset, and diverting gdTCR-expressing precursors to the ab fate. Altogether, this is a very thorough, thoughtfully interpreted study that adds significantly to our understanding of the contribution of the SLAM-SAP pathway to lineage specification. A particularly interesting element is the role of SLAM-SAP in preventing gd17 progenitors from switching fates and adopting the ab fate.

One thing to keep in mind in assessing the ultimate fate of the "ab wannabe cells" is that mechanisms exist to silence the gd TCR as cells differentiate to the DP stage and so their presence as diverted DP cells may not be evident by staining for gdTCR expression - and will only be evident transcriptomically.

Strengths:

This is an exceedingly well-designed and thorough study that significantly enriches our understanding of gd T cell development.

Weaknesses:

There are no major weaknesses identified by this reviewer.

  1. Howard Hughes Medical Institute
  2. Wellcome Trust
  3. Max-Planck-Gesellschaft
  4. Knut and Alice Wallenberg Foundation