Perforin and IL-2 Upregulation Define Qualitative Differences among Highly Functional Virus-Specific Human CD8(+) T Cells
Abstract
The prevailing paradigm of T lymphocyte control of viral replication is that the protective
capacity of virus-specific CD8(+) T cells is directly proportional to the number of
functions they can perform, with IL-2 production capacity considered critical. Having
recently defined rapid perforin upregulation as a novel effector function of antigen-specific
CD8(+) T cells, here we sought to determine whether new perforin production is a component
of polyfunctional CD8(+) T cell responses that contributes to the control of several
human viral infections: cytomegalovirus (CMV), Epstein-Barr virus (EBV), influenza
(flu), and adenovirus (Ad). We stimulated normal human donor PBMC with synthetic peptides
whose amino acid sequences correspond to defined CTL epitopes in the aforementioned
viruses, and then used polychromatic flow cytometry to measure the functional capacity
and the phenotype of the responding CD8(+) T cells. While EBV and flu-specific CD8(+)
T cells rarely upregulate perforin, CMV-specific cells often do and Ad stimulates
an exceptionally strong perforin response. The differential propensity of CD8(+) T
cells to produce either IL-2 or perforin is in part related to levels of CD28 and
the transcription factor T-bet, as CD8(+) T cells that rapidly upregulate perforin
harbor high levels of T-bet and those producing IL-2 express high amounts of CD28.
Thus, "polyfunctional'' profiling of antigen-specific CD8(+) T cells must not be limited
to simply the number of functions the cell can perform, or one particular memory phenotype,
but should actually define which combinations of memory markers and functions are
relevant in each pathogenic context.
Type
Other articleSubject
epstein-barr-virushepatitis-c virus
transcription factor
lineage
commitment
immune-responses
b-virus
memory
effector
bet
lymphocytes
infectious diseases
microbiology
parasitology
virology
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https://hdl.handle.net/10161/4595Published Version (Please cite this version)
10.1371/journal.ppat.1000798Citation
Makedonas,George;Hutnick,Natalie;Haney,Danielle;Amick,Alexandra C.;Gardner,Jay;Cosma,Gabriela;Hersperger,Adam
R.;Dolfi,Douglas;Wherry,E. John;Ferrari,Guido;Betts,Michael R.. 2010. Perforin and
IL-2 Upregulation Define Qualitative Differences among Highly Functional Virus-Specific
Human CD8(+) T Cells. Plos Pathogens 6(3): e1000798-e1000798.
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Show full item recordScholars@Duke
Guido Ferrari
Professor in Surgery
The activities of the Ferrari Laboratory are based on both independent basic research
and immune monitoring studies. The research revolves around three main areas of interest:
class I-mediated cytotoxic CD8+ T cell responses, antibody-dependent cellular cytotoxicity
(ADCC), gene expression in NK and T cellular subsets upon infection with HIV-1. With
continuous funding over the last 11 years from the NIH and Bill & Melinda Gates Foundation
along with many other productive collaborations wi

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