Molecular profiling of cytomegalovirus-induced human CD8+ T cell differentiation
Kirsten M.L. Hertoghs, … , Ineke J.M. ten Berge, René A.W. van Lier
Kirsten M.L. Hertoghs, … , Ineke J.M. ten Berge, René A.W. van Lier
Published October 1, 2010
Citation Information: J Clin Invest. 2010;120(11):4077-4090. https://doi.org/10.1172/JCI42758.
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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 1

HCMV induces major changes in gene expression after priming of naive CD8+ T cells that are largely maintained during latency.

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HCMV induces major changes in gene expression after priming of naive CD8...
(A) Graphical representation of hierarchical clustering by Rosetta Resolver. Shown are mean changes in transcript levels of CMV-specific CD8+ cells induced at the peak and 1 year after primary infection as well as in latency, compared with naive samples. The gene set included all genes that were significant after the Benjamini-Hochberg correction for multiple testing (P ≤ 0.05) and were more than 2-fold up- or downregulated compared with RNA of naive CD8+ cells at 1 of the 4 time points. Samples were clustered together with mean expression value for total effector (CD8+CD45RA+CD27–) cells of HCMV+ healthy donors. (B) BioVenn (82) diagram showing the distribution between peak, 1 year (transplant recipient), and latency stage of infection (healthy donor) of all 1,613 genes that were significantly altered (2-fold change and corrected P ≤ 1 × 10–10). The relative size of the circle represents the size of the respective group. (C) Average gene expression patterns (± 1 SD) of the 4 clusters found using the CLICK algorithm. The gene set included all genes greater than 10-fold up- or downregulated compared with RNA of naive CD8+ T cells at 1 of the 4 time points with corrected P ≤ 1 × 10–10. n for each cluster is shown.