T-cells produce acidic niches in lymph nodes to suppress their own effector functions

Hao Wu, Veronica Estrella, Matthew Beatty, Dominique Abrahams, Asmaa El-Kenawi, Shonagh Russell, Arig Ibrahim-Hashim, Dario Livio Longo, Yana K. Reshetnyak, Anna Moshnikova, Oleg A. Andreev, Kimberly Luddy, Mehdi Damaghi, Krithika Kodumudi, Smitha R. Pillai, Pedro Enriquez-Navas, Shari Pilon-Thomas, Pawel Swietach () and Robert J. Gillies ()
Additional contact information
Hao Wu: H. Lee Moffitt Cancer Center and Research Institute
Veronica Estrella: H. Lee Moffitt Cancer Center and Research Institute
Matthew Beatty: H. Lee Moffitt Cancer Center and Research Institute
Dominique Abrahams: H. Lee Moffitt Cancer Center and Research Institute
Asmaa El-Kenawi: H. Lee Moffitt Cancer Center and Research Institute
Shonagh Russell: H. Lee Moffitt Cancer Center and Research Institute
Arig Ibrahim-Hashim: H. Lee Moffitt Cancer Center and Research Institute
Dario Livio Longo: National Research Council of Italy (CNR)
Yana K. Reshetnyak: University of Rhode Island
Anna Moshnikova: University of Rhode Island
Oleg A. Andreev: University of Rhode Island
Kimberly Luddy: H. Lee Moffitt Cancer Center and Research Institute
Mehdi Damaghi: H. Lee Moffitt Cancer Center and Research Institute
Krithika Kodumudi: H. Lee Moffitt Cancer Center and Research Institute
Smitha R. Pillai: H. Lee Moffitt Cancer Center and Research Institute
Pedro Enriquez-Navas: H. Lee Moffitt Cancer Center and Research Institute
Shari Pilon-Thomas: H. Lee Moffitt Cancer Center and Research Institute
Pawel Swietach: University of Oxford
Robert J. Gillies: H. Lee Moffitt Cancer Center and Research Institute

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract The acidic pH of tumors profoundly inhibits effector functions of activated CD8 + T-cells. We hypothesize that this is a physiological process in immune regulation, and that it occurs within lymph nodes (LNs), which are likely acidic because of low convective flow and high glucose metabolism. Here we show by in vivo fluorescence and MR imaging, that LN paracortical zones are profoundly acidic. These acidic niches are absent in athymic Nu/Nu and lymphodepleted mice, implicating T-cells in the acidifying process. T-cell glycolysis is inhibited at the low pH observed in LNs. We show that this is due to acid inhibition of monocarboxylate transporters (MCTs), resulting in a negative feedback on glycolytic rate. Importantly, we demonstrate that this acid pH does not hinder initial activation of naïve T-cells by dendritic cells. Thus, we describe an acidic niche within the immune system, and demonstrate its physiological role in regulating T-cell activation.

Date: 2020
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DOI: 10.1038/s41467-020-17756-7

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