Loss of immunological control at CD28 superfamily checkpoints links brain and peripheral immunity to depressive-like behaviors in animal models.

Interactions between the nervous and immune systems play a central role in depression, yet the mechanisms integrating neuroimmune signaling remain poorly understood. Here, we investigated the regulation of immune checkpoints in three mechanistically distinct models of depressive-like behavior: treatment-resistant Wistar Kyoto rats, Wistar rats exposed to chronic restraint stress, and Porphyromonas gingivalis-infected C57BL/6 mice. Using integrated molecular analyses that combine targeted gene and protein measurements with transcriptional profiling, we identified alterations in immune checkpoint signaling within the CD28 superfamily that were associated with the severity of depressive-like phenotypes across selected models. Across all models, immune signaling showed concurrent costimulatory activation (CD28, ICOS) alongside alterations in the PD-1/PD-L1 axis, including increased PD-1 levels in peripheral blood and changes in PD-L1 expression in the brain. Transcriptional alterations in CD28-superfamily regulators and related immune modulators further indicated the coexistence of immune activation and partial exhaustion signatures, consistent with chronic immune dysregulation rather than a uniform inflammatory response. Among the investigated immune checkpoints, reduced PD-L1 expression in the WKY model represented the most consistent finding across targeted and transcriptomic analyses. Despite model-specific transcriptional differences, the expression levels of selected immune checkpoint-related genes were associated with performance in the novel object recognition test. Together, these findings suggest that alterations in the CD28 immune checkpoint (PD-1/PD-L1, CD28/CD80, ICOS/ICOSL) network accompany depressive-like phenotypes and suggest that impaired immune checkpoint control may contribute to cognitive dysfunction in depressive disorders. Targeting immune checkpoint pathways may therefore represent a promising direction for future therapeutic strategies in treatment-resistant depression.