Perforin and IL-2 Upregulation Define Qualitative Differences among Highly Functional Virus-Specific Human CD8+ T Cells

PLoS Pathogens

Natalie Hutnick¹  Jay Gardner¹  Alexandra C. Amick¹  Michael R. Betts¹  Danielle Haney¹  George Makedonas¹  Gabriela Cosma¹  Adam R. Hersperger¹  Guido Ferrari²  Douglas Dolfi³  E. John Wherry³ 

[1] Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;Department of Surgical Sciences, Duke University Medical Center, Durham, North Carolina, United States of America;The Wistar Institute, Philadelphia, Pennsylvania, United States of America

关键词: T cells;    Cytotoxic T cells;    Epstein-Barr virus;    California;    Human cytomegalovirus;    Memory T cells;    Cell degranulation;    Infectious disease control;   

DOI  :  10.1371/journal.ppat.1000798

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY