Fas Ligand-mediated cytotoxicity of CD4+ T cells during chronic retrovirus infection

Anna Malyshkina,Gennadiy Zelinskyy,Elisabeth Littwitz-Salomon,Kim J Hasenkrug,Kathrin Sutter,Sonja Windmann,Hendrik Streeck,Simone Schimmer,Annette Paschen,Ulf Dittmer

doi:10.1038/s41598-017-08578-7

Abstract

CD4+ helper T cells and cytotoxic CD8+ T cells are key players for adaptive immune responses against acute infections with retroviruses. Similar to textbook knowledge the most important function of CD4+ T cells during an acute retrovirus infection seems to be their helper function for other immune cells. Whereas there was no direct anti-viral activity of CD4+ T cells during acute Friend Virus (FV) infection, they were absolutely required for the control of chronic infection. During chronic FV infection a population of activated FV-specific CD4+ T cells did not express cytotoxic molecules, but Fas Ligand that can induce Fas-induced apoptosis in target cells. Using an MHC II-restricted in vivo CTL assay we demonstrated that FV-specific CD4+ T cells indeed mediated cytotoxic effects against FV epitope peptide loaded targets. CD4 + CTL killing was also detected in FV-infected granzyme B knockout mice confirming that the exocytosis pathway was not involved. However, killing could be blocked by antibodies against FasL, which identified the Fas/FasL pathway as critical cytotoxic mechanism during chronic FV infection. Interestingly, targeting the co-stimulatory receptor CD137 with an agonistic antibody enhanced CD4+ T cell cytotoxicity. This immunotherapy may be an interesting new approach for the treatment of chronic viral infections.

Highlights

Viral replication and spread in the acute phase of an infection is usually under the control of CD8+ T cells
We previously developed an MHC class II-restricted in vivo cytotoxicity assay to detect Friend Virus (FV)-specific killing of target cells loaded with the immunodominant FV CD4+ T cell epitope H19 envelope epitope alone (H19-Env)
CD4+ T cells play an important role as helper cells in many acute infections. This cell population is facilitating neutralizing antibodies (NAb) responses, which are necessary for recovery from acute FV infection[37]

Summary

Introduction

Viral replication and spread in the acute phase of an infection is usually under the control of CD8+ T cells. To determine whether virus-specific CD4+ T cells remained detectable during chronic FV infection, spleen and lymph node cells were analyzed using MHC II tetramer (Tet II) (constructed for the FV H19-Env epitope). These results suggested that effector CD4+ T cells might mediate their anti-viral effects during chronic FV infection via the Fas/FasL cytotoxicity pathway.

Results

Conclusion