Lysosomal adaptation to extracellular acidity compromises CD8+ T cell cytotoxicity
- 1Inserm
Abstract
Extracellular acidosis is a hallmark of aggressive tumors and suppresses cytotoxic-T lymphocyte (CTL)-mediated killing, but how sustained acid exposure reshapes T cell cytotoxicity is poorly understood. Here we show that chronic acidosis drives lysosomal remodeling in human CD8+ T cells, converting the lysosome into a proton sink whose adaptation ultimately impairs killing by depleting the intracellular granzyme B reservoir through constitutive vesicle release. Quantitative proteomics of CD8+ T cells cultured at pH 6.5 identified lysosomes as the dominant target of acid-driven remodeling: CTLs upregulated the V1 sector of the vacuolar H+-ATPase and hyper-acidified the lysosomal lumen. The remodeled compartment accumulated lysosomal membrane proteins (LAMP1, LAMP2, CD63, CD68) post-transcriptionally, acquired higher cathepsin abundance and increased proteolytic activity. Chronic acidity also enlarged endoplasmic reticulum (ER) and lysosomal Ca2+ stores without altering cytosolic Ca2+, and drives constitutive, Ca2+-dependent release of LAMP1+ lysosome-derived vesicles, which drains the intracellular reservoir of granzyme B, contributing to reduced CTL activity. These findings establish lysosomal adaptation as a cost of surviving extracellular acidosis and identify lysosomal hydrolase activity as a possible target for improving CTL function in the acidic tumor environment.
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BibTeX
@misc{segain2026lysosomal,
title = {{Lysosomal adaptation to extracellular acidity compromises CD8+ T cell cytotoxicity}},
author = {B. Segain and R. Conesa and C. Rollings and S. Titah and E. Paulin and A. Cozzani and A. Kasprowicz and L. Mohammadnizad and S. Gaggero and Y. Touil and I. Moraga and B. Quesnel and R. Roychoudhuri and R. Eil and L. V. Sinclair and J. Martinez and S. Mitra},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.21.760659},
url = {https://www.biorxiv.org/content/10.64898/2026.10.21.760659v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Lysosomal adaptation to extracellular acidity compromises CD8+ T cell cytotoxicity
AU - B. Segain
AU - R. Conesa
AU - C. Rollings
AU - S. Titah
AU - E. Paulin
AU - A. Cozzani
AU - A. Kasprowicz
AU - L. Mohammadnizad
AU - S. Gaggero
AU - Y. Touil
AU - I. Moraga
AU - B. Quesnel
AU - R. Roychoudhuri
AU - R. Eil
AU - L. V. Sinclair
AU - J. Martinez
AU - S. Mitra
PY - 2026
DA - 2026/10/21
PB - bioRxiv
DO - 10.64898/2026.10.21.760659
UR - https://www.biorxiv.org/content/10.64898/2026.10.21.760659v1
AB - Extracellular acidosis is a hallmark of aggressive tumors and suppresses cytotoxic-T lymphocyte (CTL)-mediated killing, but how sustained acid exposure reshapes T cell cytotoxicity is poorly understood. Here we show that chronic acidosis drives lysosomal remodeling in human CD8+ T cells, converting the lysosome into a proton sink whose adaptation ultimately impairs killing by depleting the intracellular granzyme B reservoir through constitutive vesicle release. Quantitative proteomics of CD8+ T cells cultured at pH 6.5 identified lysosomes as the dominant target of acid-driven remodeling: CTLs upregulated the V1 sector of the vacuolar H+-ATPase and hyper-acidified the lysosomal lumen. The remodeled compartment accumulated lysosomal membrane proteins (LAMP1, LAMP2, CD63, CD68) post-transcriptionally, acquired higher cathepsin abundance and increased proteolytic activity. Chronic acidity also enlarged endoplasmic reticulum (ER) and lysosomal Ca2+ stores without altering cytosolic Ca2+, and drives constitutive, Ca2+-dependent release of LAMP1+ lysosome-derived vesicles, which drains the intracellular reservoir of granzyme B, contributing to reduced CTL activity. These findings establish lysosomal adaptation as a cost of surviving extracellular acidosis and identify lysosomal hydrolase activity as a possible target for improving CTL function in the acidic tumor environment.
ER -