CD47 Expression in Natural Killer Cells Regulates Homeostasis and Modulates Immune Response to Lymphocytic Choriomeningitis Virus

Pulak Ranjan Nath,Ajeet Mandal,John M Sipes,Dragan Maric,David D Roberts,Maggie Cam,Dipasmita Pal-Nath,Arunakumar Gangaplara,Ethan M Shevach

doi:10.3389/fimmu.2018.02985

Abstract

CD47 is a ubiquitous cell surface receptor that directly regulates T cell immunity by interacting with its inhibitory ligand thrombospondin-1 and limits clearance of cells by phagocytes that express its counter-receptor signal-regulatory protein-α. Murine natural killer (NK) cells express higher levels of CD47 than other lymphocytes, but the role of CD47 in regulating NK cell homeostasis and immune function remains unclear. Cd47−/− mice exhibited depletion of NK precursors in bone marrow, consistent with the antiphagocytic function of CD47. In contrast, antisense CD47 knockdown or gene disruption resulted in a dose dependent accumulation of immature and mature NK cells in spleen. Mature Cd47−/− NK cells exhibited increased expression of NK effector and interferon gene signatures and an increased proliferative response to interleukin-15 in vitro. Cd47−/− mice showed no defect in their early response to acute Armstrong lymphocytic choriomeningitis virus (LCMV) infection but were moderately impaired in controlling chronic Clone-13 LCMV infection, which was associated with depletion of splenic NK cells and loss of effector cytokine and interferon response gene expression in Cd47−/− NK cells. Broad CD47-dependent differences in NK activation, survival, and exhaustion pathways were observed in NK cell transcriptional signatures in LCMV infected mice. These data identify CD47 as a cell-intrinsic and systemic regulator of NK cell homeostasis and NK cell function in responding to a viral infection.

Highlights

Natural killer (NK) cells are a distinct group of cytotoxic innate lymphoid cells that play significant roles as a first line of defense against pathogenic invasion and malignant cell transformation [1,2,3,4,5]
RNA expression of Itgam and Il2rb did not show any difference between the sorted WT and Cd47−/− populations (Figure S7C). These data suggest that the gene expression changes we report do not result from different mature natural killer (NK) cells (mNK)/immature NK (iNK) ratios in the sorted WT and Cd47−/− cells that were used for the RNAseq
The present data identify roles for CD47 in murine NK cell homeostasis and function in viral infection that extend beyond the passive role of CD47 as a don’t eat me signal

Summary

Introduction

Natural killer (NK) cells are a distinct group of cytotoxic innate lymphoid cells that play significant roles as a first line of defense against pathogenic invasion and malignant cell transformation [1,2,3,4,5]. These lymphocytes uniquely express inhibitory receptors including CD94 and the leukocyte immunoglobulin-like receptor family and activating receptors including NKG2D and the natural cytotoxicity receptors [6]. CD47 Regulates NK Cell Function receptors or when signals from activating and co-activating receptors overcome inhibitory signals. Though the development and function of NK cells are widely studied, our understanding of the cell intrinsic factors regulating homeostasis and function of NK cells is incomplete

Methods

Results

Conclusion