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Deficiencies in the adaptive immune system have been linked to anxiety-like behaviours and stress reactivity. Mice lacking T lymphocytes through knockout of the T cell receptor (TCR) β and δ chains were compared to wild type C57Bl/6 mice. Central stress circuitry gene expression was assessed following repeated restraint stress. TCRβ−/−δ−/− mice showed an increased baseline plasma corticosterone and exaggerated changes in stressrelated gene expression after repeated restraint stress. Sexual dimorphic stress responses were observed in wildtype C57Bl/6 mice but not in TCRβ−/−δ−/− mice. These data suggest that T cell-brain interactions influence sex-differences in CNS stress circuitry and stress reactivity.