TY - JOUR T1 - Lymph Nodes Inhibit T-cell Effector Functions Locally by Establishing Acidic Niches JF - bioRxiv DO - 10.1101/689604 SP - 689604 AU - Hao Wu AU - Veronica Estrella AU - Pedro Enriquez-Navas AU - Asmaa El-Kenawi AU - Shonagh Russell AU - Dominique Abrahams AU - Arig Ibrahim-Hashim AU - Dario Longo AU - Yana Reshetnyak AU - Kimberly Luddy AU - Mehdi Damaghi AU - Smitha Ravindranadhan Pillai AU - Matthew Beatty AU - Shari Pilon-Thomas AU - Pawel Swietach AU - Robert J. Gillies Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/07/02/689604.abstract N2 - Lymph nodes are an essential component of the adaptive immune response where antigen-presenting cells are closely housed with their cognate effector cells. Protection of lymph node resident cells from activated immune cells in such close quarters would need to be robust and reversible. Effector functions of T-cells are profoundly and reversibly inhibited by an acidic microenvironment. The underlying mechanisms of this inhibition are unknown, but may relate to glycolysis, which is obligatory for expression of effector functions. Here, we demonstrate that acidification rapidly and potently inhibits monocarboxylate transporter-dependent lactic acid efflux, which dually inhibits glycolysis by end-product accumulation and by reducing cytoplasmic pH. Based on the robustness of these responses, we propose that acid-evoked T-cell inhibition is physiologically important, and that lymph nodes are a natural site for such modulation. Using multiple imaging techniques, we show that paracortical T-zones of lymph nodes are highly acidic. We further show that T-cells can be activated by dendritic cells at low pH, and their effector functions are restored rapidly upon increasing pH. Thus, we describe a novel physiological mechanism whereby activated T-cells are kept in stasis by acidosis whilst resident in lymph nodes. ER -