Lineage-specific immune checkpoint dynamics define a context-dependent regulatory framework with translational relevance in human γδ T cells.

Authors

Anna Maria Corsale, Marta Di Simone, Juan Pablo Cerapio, Elena Lo Presti, Gabriele Pizzolato, Claudia Avellone, Costanza Dieli, Salvatore Marchiafava, Laura Di Paola, Francesco Dieli, Serena Meraviglia

Published in

Journal of translational medicine. Volume 24. Issue 1. Sep 30, 2026. Epub Sep 30, 2026.

Abstract

Immune checkpoint receptors (ICRs) are widely used as markers of T-cell exhaustion, yet their interpretation remains context-dependent and is poorly described in γδ T cells. Here, we investigated the dynamics, functional impact, and differentiation-associated distribution of ICRs across human γδ and αβ T-cell subsets.
Peripheral blood mononuclear cells from healthy donors were stimulated in vitro to assess ICR dynamics in γδ and αβ T-cell subsets by flow cytometry. Functional effects of PD-1 and TIM-3 blockade were evaluated through proliferation, cytokine production, and degranulation assays. In parallel, previously published single-cell RNA-sequencing datasets of tumor-infiltrating γδ and CD8 T cells were subjected to secondary bioinformatic analysis to characterize differentiation-associated ICR expression patterns and their modulation following immune checkpoint blockade (ICB) therapy.
ICR expression was regulated in a receptor-, lineage- and context-dependent manner. Polyclonal stimulation induced broad ICR upregulation, whereas phosphoantigen-driven Vδ2 T cell expansion resulted in a selective profile with sustained TIM-3 expression and transient modulation of PD-1 and TIGIT. Checkpoint distribution was structured across differentiation states, with TIGIT enriched in antigen-experienced subsets, LAG-3 and TIM-3 in naive compartments, and PD-1 broadly expressed. PD-1 blockade was associated with donor-dependent trends toward increased proliferation and cytokine production, particularly under IL-15 stimulation, whereas TIM-3 inhibition showed variable effects and combined blockade did not produce a consistent additive response. Single-cell transcriptomic analyses revealed that tumor-infiltrating γδ T cells displayed heterogeneous ICR expression across differentiation states, whereas CD8 T cells showed a more progressive pattern of checkpoint expression. Because classical exhaustion-associated transcriptional and epigenetic programs were not evaluated, these patterns neither establish nor exclude the presence of exhausted γδ T-cell subsets. ICB therapy was associated with persistence or upregulation of alternative checkpoints.
These findings indicate that ICR expression in γδ T cells is dynamically shaped by activation, differentiation, and environmental context. However, ICR expression alone is insufficient to define or exclude a state of T-cell exhaustion.

PMID:
42823731
Bibliographic data and abstract were imported from PubMed on 02 Oct 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.