Open AccessFas Ligand-mediated cytotoxicity of CD4+ T cells during chronic retrovirus infection
Author(s) -
Malyshkina A.I. Malyshkina,
Elisabeth Littwitz-Salomon,
Kathrin Sutter,
Gennadiy Zelinskyy,
Sonja Windmann,
Simone Schimmer,
Annette Paschen,
Hendrik Streeck,
Kim J. Hasenkrug,
Ulf Dittmer
Publication year - 2017
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/s41598-017-08578-7
Subject(s) - cytotoxic t cell , granzyme b , fas ligand , ctl* , biology , granzyme , immune system , perforin , cd8 , immunology , interleukin 21 , epitope , antigen presenting cell , t cell , virology , antigen , apoptosis , in vitro , programmed cell death , biochemistry
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.