SIRPγ promotes CD8⁺ T cell exhaustion via metabolic-epigenetic reprogramming in tuberculous pleural effusion

Abstract Previous studies have shown that signal regulatory protein γ (SIRPγ) is an important regulatory factor for T cell function. However, its expression and biological role in tuberculous pleural effusion (TPE) remain unknown. In this study, we find that the level of SIRPγ is significantly upregulated in TPE compared to non-TPE. Furthermore, we demonstrate SIRPγ involvement in TPE pathogenesis through the induction of CD8⁺ T cell exhaustion. Mechanistically, SIRPγ interacts with CD47 to activate the phosphatidylinositol 3/kinase-protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, leading to the upregulation of phosphoglycerate dehydrogenase (PHGDH) and the enhancement of serine metabolism. Serine, in turn, facilitates S-adenosylmethionine (SAM)-dependent trimethylation of histone H3 lysine 4 (H3K4me3) epigenetic modification at the NFATC2 locus. This modification, in coordination with TCR-induced calcium signaling, promotes NFATC2 activation, ultimately driving the expression of exhaustion-associated transcription factors and immunosuppressive receptors. Together, our findings identify SIRPγ as a regulator of CD8⁺ T cell exhaustion in TPE and suggest its potential as a predictive biomarker for TPE diagnosis.