Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects

By A. Sylwester, Bridget L. Mitchell, J. Edgar, Cara Taormina, Christian Pelte, F. Ruchti, P. Sleath, K. Grabstein, N. Hosken, F. Kern and 2 more. Journal of Experimental Medicine, 2005

1,441 citations recorded by the source corpus.

Human cytomegalovirus (HCMV) infections of immunocompetent hosts are characterized by a dynamic, life-long interaction in which host immune responses, particularly of T cells, restrain viral replication and prevent disease but do not eliminate the virus or preclude transmission. Because HCMV is among the largest and most complex of known viruses, the T cell resources committed to maintaining this balance have never been characterized completely. Here, using cytokine flow cytometry and 13,687 overlapping 15mer peptides comprising 213 HCMV open reading frames (ORFs), we found that 151 HCMV ORFs were immunogenic for CD4+ and/or CD8+ T cells, and that ORF immunogenicity was influenced only modestly by ORF expression kinetics and function. We further documented that total HCMV-specific T cell responses in seropositive subjects were enormous, comprising on average ∼10% of both the CD4+ and CD8+ memory compartments in blood, whereas cross-reactive recognition of HCMV proteins in seronegative individuals was limited to CD8+ T cells and was rare. These data provide the first glimpse of the total human T cell response to a complex infectious agent and will provide insight into the rules governing immunodominance and cross-reactivity in complex viral infections of humans.

Subfields: Epidemiology, Virology

View Paper: https://www.semanticscholar.org/paper/6e5c2eb3a690f78ca656be43e8ac02715af56d2f

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In Epidemiology

1. Atul J. Butte
2. Jonathan S. Weissman
3. Nicholas T. Ingolia
4. C. Hetz
5. G. Hotamışlıgil

In Virology

1. V. Appay
2. D. Sauce

Citations in the corpus

• Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. (2013, neutral): “T-cell reactivity is directed toward a wide range of CMV antigens such as pp65, pp50, IE-1, gB, and others (57, 77).”
• Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms (2021, background): “In a separate study, Sylwester et al. (2005) found that approximately 10% of CD4+ and CD8+ memory T cells in CMV seropositive subjects can be directed against the virus.”
• Ribosome profiling reveals pervasive translation outside of annotated protein-coding genes. (2014, background): “We reasoned that, if humans with a history of CMV infection displayed T cell responses against novel peptides, as they do against canonical CMV proteins (Sylwester et al., 2005), it would indicate that these peptides were produced in the course of the normal viral life cycle in a human host.”
• Variation in the human immune system is largely driven by non-heritable influences (2015, background): “As an example, the lifelong need to control CMV seems to cause a broad shift in the magnitude and complexity of many cell subsets (Chidrawar et al., 2009; Wills et al., 2011), and 10% of all T cells in CMV+ individuals can be directed against this virus (Sylwester et al., 2005).”
• The “Silent” Global Burden of Congenital Cytomegalovirus (2013, background): “immune system (181), major targets include the pp65 tegument”
• Immune activation and inflammation in HIV‐1 infection: causes and consequences (2008, background): “The anti-CMV response appears to monopolize a significant fraction of the whole T cell repertoire [97], so that it might compromise the response to other antigens by shrinking the remaining T cell repertoire and reducing T cell diversity.”