(256) The Surprising Role of SIRPα in T Cell Responses During Acute and Chronic Retroviral Infection

Introduction/Rationale: 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.