Molecular profiling of cytomegalovirus-induced human CD8+ T cell differentiation
Kirsten M.L. Hertoghs, Perry D. Moerland, Amber van Stijn, Ester B.M. Remmerswaal, Sila L. Yong, Pablo J.E.J. van de Berg, S. Marieke van Ham, Frank Baas, Ineke J.M. ten Berge, René A.W. van Lier
Kirsten M.L. Hertoghs, Perry D. Moerland, Amber van Stijn, Ester B.M. Remmerswaal, Sila L. Yong, Pablo J.E.J. van de Berg, S. Marieke van Ham, Frank Baas, Ineke J.M. ten Berge, René A.W. van Lier
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Research Article Virology

Molecular profiling of cytomegalovirus-induced human CD8+ T cell differentiation

Abstract

CD8+ T cells play a critical role in the immune response to viral pathogens. Persistent human cytomegalovirus (HCMV) infection results in a strong increase in the number of virus-specific, quiescent effector-type CD8+ T cells with constitutive cytolytic activity, but the molecular pathways involved in the induction and maintenance of these cells are unknown. We show here that HCMV infection induced acute and lasting changes in the transcriptomes of virus-reactive T cells collected from HCMV-seropositive patients at distinct stages of infection. Enhanced cell cycle and metabolic activity was restricted to the acute phase of the response, but at all stages, HCMV-specific CD8+ T cells expressed the Th1-associated transcription factors T-bet (TBX21) and eomesodermin (EOMES), in parallel with continuous expression of IFNG mRNA and IFN-γ–regulated genes. The cytolytic proteins granzyme B and perforin as well as the fractalkine-binding chemokine receptor CX3CR1 were found in virus-reactive cells throughout the response. During HCMV latency, virus-specific CD8+ T cells lacked the typical features of exhausted cells found in other chronic infections. Persistent effector cell traits together with the permanent changes in chemokine receptor usage of virus-specific, nonexhausted, long-lived CD8+ T cells may be crucial to maintain lifelong protection from HCMV reactivation.

Authors

Kirsten M.L. Hertoghs, Perry D. Moerland, Amber van Stijn, Ester B.M. Remmerswaal, Sila L. Yong, Pablo J.E.J. van de Berg, S. Marieke van Ham, Frank Baas, Ineke J.M. ten Berge, René A.W. van Lier

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Figure 4

Transcription factors involved in effector molecule production are highly upregulated in HCMV-specific cells.

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Transcription factors involved in effector molecule production are highl...
(A) HCMV-specific cells during a primary response were stained by tetramers for 2 epitopes of HCMV, IE and pp65, and EBV BMLF1 as a control. In latency, an influenza (FLU) tetramer and the pp65 tetramer, respectively, were used to visualize memory cells that remain after the infection is cleared. EBV-specific cells were stained by the BMLF1 tetramer. Numbers depict the percentage of CD8+ cells or tetramer+ cells within the CD8+ population. Histograms visualize T-bet measured in the tetramer+ samples and (C) in total effector-type (CD8+CD45RA+CD27–) and memory-type (CD8+CD45RA–CD27+) cells in latency. Shown is 1 representative patient of 3 and 1 representative healthy donor of 4 analyzed. (B) During latency, total effector and memory cells were sorted, and quantitative PCR was performed to measure transcription factors T-bet, Eomes, and Blimp-1. Graphs represent mean and SD of 3 donors analyzed. Filled gray histograms denote staining of naive CD8+ T cells.