The Surprising Role of SIRPα in T Cell Responses During Acute and Chronic Retroviral Infection 2334984

Abstract Introduction Friend virus infection of mice induces Tregs, facilitating the establishment of chronic infection and CD8+ T cell dysfunction. We reported that splenic FV-specific PD-1+CD8+ T cells expressing SIRPα maintain function, unexpected because SIRPα is an inhibitory myeloid receptor not previously described on T cells. This study further explores the functional capability of SIRPα+ and SIRPα- T cells. Methods Tissues from mice, infected with FV (with naïve controls), were harvested during acute or chronic phase and analyzed by flow cytometry for complex multiparametric immune cell analysis. Liver SIRPα- CD8+ T cells were examined for CTL activity. SIRPα+ and SIRPα- Tregs were compared for suppression. Furthermore, we performed transcriptional profile analysis on these subsets. Results We now demonstrate a more complicated view of SIRPα expression on T cells, discovering that expression on CD8+ T cells is tissue-specific, with expression induced in the spleen but not liver. The SIRPα- T cells from the livers of chronically infected mice are equivalently cytolytic and activated compared to splenic SIRPα+ T cells. In addition, we now demonstrate that SIRPα is expressed on CD4+ Foxp3- T helper and Foxp3+ Tregs during acute infection and identifies cells with distinct functional capabilities. Interestingly, SIRPα expressing T helpers have a unique transcriptional profile and appear to have an increased helper capacity. Additionally, SIRPα+Foxp3+ Tregs exhibit enhanced ability to suppress CD8+ T cell proliferation and are upregulated for multiple activation and chemokine pathways. Conclusion We now show that SIRPα expression, the ligand for CD47 and commonly associated with myeloid cells, occurs on CD8+ and CD4+ T cells in a tissue-specific manner and correlates with distinctive functional capacity. Recently CD47 blockade failed in phase III clinical trials due to increased infection-related deaths, highlighting the need to fully understand this complex immune checkpoint in the context of viral infection. Funding Source Division of Intramural Research, NIAID AI000753 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)