Tweet
J Virol. 2015 Feb 25. pii: JVI.03478-14. [Epub ahead of print]
Infection History Determines the Differentiation State of Human CD8+ T-cells.
van Aalderen MC1, Remmerswaal EB2, Verstegen NJ2, Hombrink P3, Ten Brinke A3, Pircher H4, Kootstra NA5, Ten Berge IJ2, van Lier RA3.
Author information
Abstract
After resolution of the acute phase of infection, otherwise quiescent antigen-experienced CD8+ T-cells confer rapid protection upon re-infection with viral pathogens, or in case of persistent viruses, help to maintain control of the infection. Depending on the type of virus, antigen-specific CD8+ T-cells have distinct traits, ranging from typical memory cell properties in the case of rapidly cleared viruses, to immediate effector functions for persistent viruses. We here show that both the differentiation stage defined by the expression of cell surface markers, such as CD45RA, CCR7, CD28 and CD27 and distinct expression levels of T-bet and eomesodermin (Eomes) predict the functional profile of antigen-experienced CD8+ T cells. Furthermore, virus-specific CD8+ T cells targeting different respiratory syncytial virus-, influenza A virus-, Epstein-Barr virus-, human cytomegalovirus- and HIV-1-specific epitopes, adopt distinct T-bet and Eomes expression patterns that appear to be installed early during the primary response. Importantly, the associations between surface phenotype, T-bet/Eomes expression levels and expression of markers that predict CD8+ T-cell function, change according to viral infection history, particularly against the background of human immunodeficiency virus-1, and to lesser extent, also of human cytomegalovirus and/or Epstein-Barr virus infection. Thus, functionality of human antigen-experienced CD8+ T cells follows at least two dimensions, one outlined by the surface phenotype and another by the T-bet/Eomes expression level, which is determined by previous or persistent viral challenges.
IMPORTANCE:
Functional human CD8+ T-cell subsets have been defined using surface markers like CD45RA, CCR7, CD28 and CD27. However, the induction of function-defining traits, like granzyme B expression, is controlled by transcription factors like T-bet and Eomes. Here we describe how T-bet and Eomes levels distinctly relate to the expression of molecules predictive for CD8+ T-cell function in a surface phenotype-independent manner. Importantly, we found that central-memory- and effector-memory CD8+ T-cell subsets differentially express T-bet and Eomes and molecules predictive for function according to viral infection history, particularly so in the context of HIV-1 infection and to lesser extent also of latent EBV and/or hCMV -infected, otherwise healthy adults. Finally, we show that the distinct phenotypes and T-bet/Eomes levels of different virus-specific CD8+ T-cell populations are imprinted early during the acute phase of primary infection in vivo. These findings broaden our understanding of CD8+ T-cell differentiation.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 25717102 [PubMed - as supplied by publisher]
Infection History Determines the Differentiation State of Human CD8+ T-cells.
van Aalderen MC1, Remmerswaal EB2, Verstegen NJ2, Hombrink P3, Ten Brinke A3, Pircher H4, Kootstra NA5, Ten Berge IJ2, van Lier RA3.
Author information
Abstract
After resolution of the acute phase of infection, otherwise quiescent antigen-experienced CD8+ T-cells confer rapid protection upon re-infection with viral pathogens, or in case of persistent viruses, help to maintain control of the infection. Depending on the type of virus, antigen-specific CD8+ T-cells have distinct traits, ranging from typical memory cell properties in the case of rapidly cleared viruses, to immediate effector functions for persistent viruses. We here show that both the differentiation stage defined by the expression of cell surface markers, such as CD45RA, CCR7, CD28 and CD27 and distinct expression levels of T-bet and eomesodermin (Eomes) predict the functional profile of antigen-experienced CD8+ T cells. Furthermore, virus-specific CD8+ T cells targeting different respiratory syncytial virus-, influenza A virus-, Epstein-Barr virus-, human cytomegalovirus- and HIV-1-specific epitopes, adopt distinct T-bet and Eomes expression patterns that appear to be installed early during the primary response. Importantly, the associations between surface phenotype, T-bet/Eomes expression levels and expression of markers that predict CD8+ T-cell function, change according to viral infection history, particularly against the background of human immunodeficiency virus-1, and to lesser extent, also of human cytomegalovirus and/or Epstein-Barr virus infection. Thus, functionality of human antigen-experienced CD8+ T cells follows at least two dimensions, one outlined by the surface phenotype and another by the T-bet/Eomes expression level, which is determined by previous or persistent viral challenges.
IMPORTANCE:
Functional human CD8+ T-cell subsets have been defined using surface markers like CD45RA, CCR7, CD28 and CD27. However, the induction of function-defining traits, like granzyme B expression, is controlled by transcription factors like T-bet and Eomes. Here we describe how T-bet and Eomes levels distinctly relate to the expression of molecules predictive for CD8+ T-cell function in a surface phenotype-independent manner. Importantly, we found that central-memory- and effector-memory CD8+ T-cell subsets differentially express T-bet and Eomes and molecules predictive for function according to viral infection history, particularly so in the context of HIV-1 infection and to lesser extent also of latent EBV and/or hCMV -infected, otherwise healthy adults. Finally, we show that the distinct phenotypes and T-bet/Eomes levels of different virus-specific CD8+ T-cell populations are imprinted early during the acute phase of primary infection in vivo. These findings broaden our understanding of CD8+ T-cell differentiation.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 25717102 [PubMed - as supplied by publisher]