INTRODUCTION: A growing body of research links depression to activation of immuno-inflammatory pathways. Although current antidepressants for depressive disorders show some immunomodulatory effects, exploring novel therapeutic targets remains a critical priority.

AIM(S): This study aimed to investigate the involvement of inhibitory immune checkpoint (ICP) molecules—namely programmed cell death protein 1 (PD-1) and its ligand PD-L1—as well as activatory ICPs, including Inducible T-cell COStimulator (ICOS) and CD28, in depression-like behavior using animal models.

METHOD(S): The study employed three animal models: WKY rats (treatment-resistant depression), Wistar rats subjected to 21-day chronic restraint stress (CRS), and C57BL/6 mice infected with Porphyromonas gingivalis (infection-induced depression). Untreated Wistar rats served as controls for both rat models. The protein levels of specific ICPs were measured in the hippocampal, cortical, and splenic tissues derived from the examined animals.

RESULTS: In WKY rats, increased PD-1 and decreased PD-L1 levels were observed in the spleen. Activating immune checkpoints (ICOS and CD28) were elevated in the hippocampus and spleen of WKY rats and CRS-exposed rats and in the hippocampus of P. gingivalis-infected mice. No significant changes were found in the frontal cortex. These results highlight model-specific alterations in immune checkpoint expression linked to depression-like behavior.

CONCLUSIONS: The observed alterations in immune checkpoint protein levels across different animal models suggest that ICP regulation may play a key role in the pathophysiology of depression-like behaviors. These findings highlight potential therapeutic targets involving immune checkpoint pathways for the treatment of depression.

FINANCIAL SUPPORT: This work was supported by statutory funds of the Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology PAS, and grant 2021/43/B/NZ6/02203 from the National Science Centre, Poland.