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J Immunol. 2019 Sep 1;203(5):1276-1287. doi: 10.4049/jimmunol.1900377. Epub 2019 Jul 15.

Primary EBV Infection Induces an Acute Wave of Activated Antigen-Specific Cytotoxic CD4+ T Cells.

Author information

1
Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
2
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom; and.
3
Tetramer Core Laboratory, Diabetes Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101.
4
Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; h.m.long@bham.ac.uk.

Abstract

CD4+ T cells are essential for immune protection against viruses, yet their multiple roles remain ill-defined at the single-cell level in humans. Using HLA class II tetramers, we studied the functional properties and clonotypic architecture of EBV-specific CD4+ T cells in patients with infectious mononucleosis, a symptomatic manifestation of primary EBV infection, and in long-term healthy carriers of EBV. We found that primary infection elicited oligoclonal expansions of TH1-like EBV-specific CD4+ T cells armed with cytotoxic proteins that responded immediately ex vivo to challenge with EBV-infected B cells. Importantly, these acutely generated cytotoxic CD4+ T cells were highly activated and transcriptionally distinct from classically described cytotoxic CD4+ memory T cells that accumulate during other persistent viral infections, including CMV and HIV. In contrast, EBV-specific memory CD4+ T cells displayed increased cytokine polyfunctionality but lacked cytotoxic activity. These findings suggested an important effector role for acutely generated cytotoxic CD4+ T cells that could potentially be harnessed to improve the efficacy of vaccines against EBV.

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