Absence of the “Don’t Eat Me” signal results in aberrant T cell responses to Leishmania major

Introduction/Rationale: CD47 is a ubiquitously expressed cell surface protein that regulates immune homeostasis by engaging signal regulatory protein alpha (SIRPa) on phagocytes to inhibit their activation. While the CD47-SIRPa axis is known to regulate both innate immunity and T cell responses in cancer & sterile inflammation, its role in infectious disease is poorly defined. Leishmania major (L. major) is an intracellular protozoan parasite that infects phagocytes. Macrophages and CD4+ T cells are both critical for immunity to L. major infection, so we interrogated the role that “don’t eat me” signals play in immunity to L. major.

Methods: We infected Cd47-/- & Sirpa-/- mice on a C57BL/6 background subcutaneously in each footpad and harvested draining lymph nodes & spleens at several critical time points for flow cytometry. T cell responses were assessed further by ICS & transcription factor staining.

Results: Cd47-/- & Sirpa-/- disease is severe. They present increased lesions, swelling, & parasite burden compared to controls. Decrease in T cells & increase in antigen experienced T cells is seen. IFNg & TNFa producers are reduced, likely liable for the severity. Conversely, T cell activation is increased in KO mice during acute disease (15dpi) when severity is similar.

Conclusion: Further studies are in progress to characterize why Cd47-/- & Sirpa-/- mice fail to control L. major infection despite strong early Th1 responses. This is a novel finding showing CD47-SIRPa is required for protective T cell responses to infection.