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

Hao Wu,Mehdi Damaghi,Arig Ibrahim-Hashim,Smitha R Pillai,Matthew Beatty,Krithika Kodumudi,Oleg A Andreev,Pawel Swietach,Dominique Abrahams,Asmaa El-Kenawi,Shari Pilon-Thomas,Yana K Reshetnyak,Kimberly Luddy,Dario Livio Longo,Robert J Gillies,Veronica Estrella,Shonagh Russell,Pedro Enriquez-Navas,Anna Moshnikova

doi:10.1038/s41467-020-17756-7

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.

Highlights

The acidic pH of tumors profoundly inhibits effector functions of activated CD8 + T-cells
We further show that the low extracellular pH of lymph nodes (LNs) does not impair the ability of T-cells to become activated by antigen-presenting cells (APCs), whereas it does suppress elaboration of cytokine production
The pHe of inguinal LNs in C57BL/6 (B6) mice was probed using pH-Low Insertion Peptide a short peptide that undergoes a conformational change at low pH to make it membrane penetrant, where it can be persistent[17,18,19,20,21]

Summary

Introduction

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. Lymph nodes (LNs) are anatomically and physiologically complex organs that receive inputs from both lymphatic and blood vasculatures, and consist of discrete zones for processing and activating T and B cells (Fig. 1a). Aberrant activation of densely packed T-cells can, for example, induce immunopathological responses in both lymphoid and nonlymphoid tissues and, for that reason, many checkpoints are in place to prevent overactive lymphocytes in these organs[8,9,10] While these checkpoints are active under physiological conditions, a pathologically overactive immune response can negatively impact lymph node structure and function. Without direct measurements of pH in intact LNs, the physiological significance of this postulated regulatory influence is untested

Methods

Results

Conclusion