SIRPγ modulates activation and pro-inflammatory response from naïve CD8 T cells in humans 2262

Description Signal Regulatory Protein gamma (SIRPγ) is a membrane protein expressed on T-cells in the human immune system. Variants in SIRPG is associated with autoimmune diseases and maintenance of a vaccine response long term, although its function remains unknown. We have previously shown that SIRPγ expression varies among individuals, with some having robust, intermediate, or low levels on T-cells. Functionally, SIRPγlow CD8 T cells have exaggerated pro-inflammatory responses upon sub-optimal activation, suggesting that perturbations in SIRPg levels may lead to immune dysregulation during infections and autoimmunity. To test this, we investigated whether intrinsic dysregulation of SIRPγ on naïve T-cells may drive hyper-proinflammatory responses. By knocking down SIRPγ (SIRPγ-KD) in naïve CD8 T-cells, we found reduced CD27 expression and identified a corresponding CD45RO-CD27low CD8 T cells in SIRPγlow carriers. SIRPγ-KD naïve CD8 T-cells also showed increased activation markers (CD11a, CD49d) and enhanced phosphorylation of pTyr-394 p56lck. These patterns were mirrored in ex vivo derived CD45RO-CD27low CD8 T-cells compared to CD45RO-CD27high CD8 T-cells. Finally, SIRPγ-KD naïve CD8 T-cells showed enhanced secretion of pro-inflammatory cytokines (IL-2, IL-17E, IL-32α) and chemokines (CXCL11, CXCL12). These findings highlight SIRPγ’s role in modulating naïve CD8 T-cell activation and inflammation, suggesting its potential impact on immune responses and inflammation. Funding Sources There are limited travel funds available through NIH 1R15NSO95317-01A1 NIAID Grant awarded to Dr. Sinha. This travel award will be critical for me to be able to present at AAI.