Tracheal terminal cells of <i>Drosophila</i> are immune privileged to maintain their Foxo-dependent structural plasticity.

Abstract

Respiratory organs must balance their primary function of gas exchange with the constant threat of inhaled pathogens. In the <i>Drosophila</i> tracheal system, gas exchange occurs at the tracheal terminal cells (TTCs), the functional equivalents of mammalian alveoli. While bacterial infection triggers a robust innate immune response throughout the broader airway epithelium, we reveal that TTCs are uniquely exempt from this reaction. Mechanistically, TTCs lack expression of the membrane-associated peptidoglycan recognition receptor PGRP-LC. This absence protects these highly susceptible cells from immune deficiency (Imd) pathway activation and subsequent JNK-mediated cell death, establishing TTCs as a distinct, immune-privileged niche. Ectopic immune activation via targeted <i>PGRP-LCx</i> overexpression in TTCs caused a severe reduction in branching, cellular damage, and ultimately cell death, phenotypes that were fully rescued by the depletion of AP-1 or <i>foxo</i>. Because both structural plasticity (in response to nutritional cues and hypoxia) and innate immune responses strictly require the transcription factor FoxO, we demonstrate that potent immune signaling is fundamentally incompatible with dynamic TTC remodeling. Ultimately, the immune-privileged status of TTCs represents an essential evolutionary trade-off, restricting local inflammation to preserve <i>foxo</i>-dependent structural plasticity and vital respiratory function.