T cell oxygen sensing is required for suppression of pulmonary effector responses

Authors

• D Clever
• M Askenase
• R Roychoudhuri
• Y Belkaid
• NP Restifo

Abstract

Through specification into a diversity of functional lineages T lymphocytes direct adaptive immune reactions in response to foreign antigens. Within the lungs, such reactions are not generated despite continual exposure to innocuous foreign antigens. The cell intrinsic mechanisms by which T lymphocyte behavior is modulated to promote local immune suppression within the lungs are incompletely elucidated. Here, we demonstrate the Phd family of propyl-hydroxylase proteins is critical for maintenance of immune homeostasis within the lungs. Phd1, Phd2, and Phd3 function redundantly as oxygen sensors in T lymphocytes to enable environmental oxygen to limit effector differentiation in vitro and in vivo. Mice with a T cell specific deletion of all three prolyl-hydroxylase proteins (Phd-tKO) develop spontaneous Th1-mediated immunopathology predominantly in the lungs. Following T cell receptor activation Phd-tKO CD4+ T lymphocytes, and wild-type T cells activated under limited environmental oxygen, demonstrate reduced specification into T regulatory cells (Treg), and instead default to a Th1 program as revealed by whole transcriptome RNA-sequence profiling and induction of Tbet and IFN protein expression. Additionally, Phd-tKO Treg cells infiltrating the lung had reduced production of the anti-inflammatory cytokine IL-10, indicating a role for the oxygen sensing machinery in instructing Treg suppressive capacity. These findings establish oxygen as a critical extracellular cue in the regulation of immune responses within the lungs and identify the oxygen sensing machinery as a T cell intrinsic regulatory node in immune homeostasis.

Scientific Focus Area: Immunology

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