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Acute brain dysfunction is a frequent complication in sepsis patients and is associated with long‑term neurocognitive consequences and increased mortality, yet the underlying mechanism remains unclear. Emerging evidence has suggested that β2‑microglobulin [a component of major histocompatibility complex (MHC) class I molecules] is involved in cognitive dysfunction in various neurological diseases. Therefore, the present study tested the hypothesis that β2‑microglobulin in the brain also mediates sepsis‑induced cognitive impairment. In the present study, wild‑type and antigen processing 1 (Tap1)‑deficient mice (Tap1‑/‑) were subjected to cecal ligation and puncture (CLP). Survival rate, cognitive function, and biochemical analysis were performed at the indicated time points. The data revealed that CLP induced anxiety‑like behavior and impaired hippocampal‑dependent contextual memory in wild‑type mice, which was accompanied by hippocampal microglial activation, increased level of interleukin‑1β, and decreased concentrations of brain derived neurotrophic factor and postsynaptic density protein 95. Notably, it was demonstrated that Tap1‑/‑ mice with reduced cell surface expression of MHC I protected mice from anxiety‑like behavior and impaired hippocampal‑dependent contextual memory and reversed most of these biochemical parameters following sepsis development. In summary, the results of the present study suggest that β2‑microglobulin negatively regulates cognitive impairment in an animal model of sepsis induced by CLP. [ABSTRACT FROM AUTHOR]