LAG3 stabilizes regulatory T cells' grip on antigen-presenting cell membrane and aids in MHCII trogocytosis

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Presentation Time: 02:15 PM - 03:30 PM
Poster Board Number: B1014
Abstract ID: 5884

Presenting Author:
Billur Akkaya , Assistant Professor

Abstract:

Current cancer therapies primarily target immune-checkpoint receptors to mitigate T cell exhaustion. Despite their utility, variable patient responses, resistance, and relapses underscore the necessity for additional therapeutic targets. Lymphocyte Activation Gene 3 (LAG3) has recently emerged as another immune checkpoint. LAG3 is expressed in the T cell synapse post-T cell receptor stimulation. While it inhibits TCR signals in effector T cells through the KIEELE motif, its role in regulatory T cell (Treg) synapses is poorly understood. Tregs form unique synapses where they pull, rip and trogocytose antigen presenting cell (APC) membrane. Due to high affinity of LAG3 for major histocompatibility complex class II (MHCII), we hypothesized that LAG3 can contribute to Tregs’ ability to trogocytose APC membrane by exerting a mechanical pull on MHCII. Indeed, lag3 knockout antigen-specific Tregs exhibited reduced trogocytosis, correlating with diminished in vivo suppressive function. APCs contacted by LAG3-deficient Tregs maintained peptide-MHCII expression and T cell priming ability. Lag3 knockout Tregs, maintaining their proliferative response and numbers ruled out any fitness defect due to absence of LAG3. Moreover, CD28 blockade deepened the trogocytosis defect, completely abolishing peptide-MHCII capture by Tregs. These findings suggest LAG3 inhibits T cell responses via cell intrinsic and extrinsic mechanisms, finely tuning antigen-specific Treg activity.