Opioid-induced fragile-like regulatory T cells contribute to withdrawal.

Dysregulation of the immune system is a cardinal feature of opioid addiction. Here, we characterize the landscape of peripheral immune cells from patients with opioid use disorder and from healthy controls. Opioid-associated blood exhibited an abnormal distribution of immune cells characterized by a significant expansion of fragile-like regulatory T cells (Tregs), which was positively correlated with the withdrawal score. Analogously, opioid-treated mice also showed enhanced Treg-derived interferon-γ (IFN-γ) expression. IFN-γ signaling reshaped synaptic morphology in nucleus accumbens (NAc) neurons, modulating subsequent withdrawal symptoms. We demonstrate that opioids increase the expression of neuron-derived C-C motif chemokine ligand 2 (Ccl2) and disrupted blood-brain barrier (BBB) integrity through the downregulation of astrocyte-derived fatty-acid-binding protein 7 (Fabp7), which both triggered peripheral Treg infiltration into NAc. Our study demonstrates that opioids drive the expansion of fragile-like Tregs and favor peripheral Treg diapedesis across the BBB, which leads to IFN-γ-mediated synaptic instability and subsequent withdrawal symptoms. [Display omitted] • An expansion of fragile-like Tregs is identified in heroin-associated blood • Opioid-induced global hypoxia triggers Treg fragility • Fabp7 protects BBB integrity from opioid-induced hyperpermeability • IFN-γ regulates opioid-induced NAc synaptic remodeling and withdrawal signs Opioids drive the peripheral expansion of fragile-like regulatory T cells that cross the blood-brain barrier and, through IFN-γ, mediate synaptic instability and subsequent withdrawal symptoms. [ABSTRACT FROM AUTHOR]