Osmotic Stress Resistance Imparts Acquired Anti‐Apoptotic Properties in Lymphocytes via Regulatory Cell Volume Mechanisms

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Apoptosis is a physiological form of cell death characterized by unique morphological and biochemical properties. A defining feature of apoptosis is the apoptotic volume decrease or AVD. Most cells have inherent volume regulatory increase (RVI) mechanisms to contest an imposed loss in cell size, however T‐cells are unique in that they do not have a RVI response. We utilized this property to explore potential regulatory roles of a RVI response in apoptosis. Exposure of immature T‐cells to hyperosmotic stress resulted in a rapid and synchronous apoptosis. Multiple rounds of osmotic stress followed by recovery in normal media resulted in a population of cells that were resistant to osmotic stress induced apoptosis. These cells were also resistant to other intrinsic apoptotic stimuli, while remaining sensitive to extrinsic apoptotic stimuli. Interestingly, these osmotic stress resistant cells showed no increase in anti‐apoptotic proteins, and released cytochrome c from their mitochondria following intrinsic apoptotic stimuli. The osmotic stress resistant cells acquired a RVI response, and inhibition of the RVI with flufenamic acid, but not amiloride compounds, restored the sensitivity of these cells to apoptosis. These results define a critical role of volume regulation mechanisms in apoptotic resistance.