CEACAM1 promotes CD8+ T cell responses and improves control of a chronic viral infection

Vishal Khairnar,Jörg Timm,Joachim R Göthert,Hilal Bhat,Tom Adomati,Ashwini Patil ,Fan Zhou,Christine Thoens,Ulf Dittmer,Philipp A Lang,Astrid M Westendorf,Judith Bezgovsek,Vikas Duhan,Cornelia Hardt,Janine D Dreesen,Piyush Sharma,Gunther Wennemuth,Bernhard B Singer,Sarah-Kim Friendrich,Gennadiy Zelinskyy,Karl S Lang

doi:10.1038/s41467-018-04832-2

Abstract

Dysfunction of CD8+ T cells can lead to the development of chronic viral infection. Identifying mechanisms responsible for such T cell dysfunction is therefore of great importance to understand how to prevent persistent viral infection. Here we show using lymphocytic choriomeningitis virus (LCMV) infection that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is fundamental for recruiting lymphocyte-specific protein kinase (Lck) into the T cell receptor complex to form an efficient immunological synapse. CEACAM1 is essential for activation of CD8+ T cells, and the absence of CEACAM1 on virus-specific CD8+ T cells limits the antiviral CD8+ T cell response. Treatment with anti-CEACAM1 antibody stabilizes Lck in the immunological synapse, prevents CD8+ T cell exhaustion, and improves control of virus infection in vivo. Treatment of human virus-specific CD8+ T cells with anti-CEACAM1 antibody similarly enhances their proliferation. We conclude that CEACAM1 is an important regulator of virus-specific CD8+ T cell functions in mice and humans and represents a promising therapeutic target for modulating CD8+ T cells.

Highlights

Dysfunction of CD8+ T cells can lead to the development of chronic viral infection
In this report we describe the involvement of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in chronic viral infection
We found that lack of CEACAM1 was correlated with deficient control of lymphocytic choriomeningitis virus (LCMV)

Summary

Introduction

Dysfunction of CD8+ T cells can lead to the development of chronic viral infection. Identifying mechanisms responsible for such T cell dysfunction is of great importance to understand how to prevent persistent viral infection. We show using lymphocytic choriomeningitis virus (LCMV) infection that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is fundamental for recruiting lymphocyte-specific protein kinase (Lck) into the T cell receptor complex to form an efficient immunological synapse. We conclude that CEACAM1 is an important regulator of virus-specific CD8+ T cell functions in mice and humans and represents a promising therapeutic target for modulating CD8+ T cells. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, CD66a, or biliary glycoprotein) is a member of the carcinoembryonic antigen (CEA) family It is engaged in cell–cell communication that affects various signal transduction processes associated with cell activation, proliferation, differentiation, and apoptosis[16,17,18]. In CD8+ T cells, filamin A interacts with CD28 and lymphocyte-specific protein kinase (Lck) and is an important molecule that modulates membrane rearrangement and CD8+ T cell signaling[34]. Whether CEACAM1 interacts with filamin A in T cells and thereby contributes to CD8+ T cell function remains unknown

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