Origin and differentiation of human memory CD8 T cells after vaccination (original) (raw)
Related papers
The Yellow Fever Virus Vaccine Induces a Broad and Polyfunctional Human Memory CD8+ T Cell Response
The Journal of Immunology, 2009
The live yellow fever vaccine (YF-17D) offers a unique opportunity to study memory CD8 ؉ T cell differentiation in humans following an acute viral infection. We have performed a comprehensive analysis of the virus-specific CD8 ؉ T cell response using overlapping peptides spanning the entire viral genome. Our results showed that the YF-17D vaccine induces a broad CD8 ؉ T cell response targeting several epitopes within each viral protein. We identified a dominant HLA-A2-restricted epitope in the NS4B protein and used tetramers specific for this epitope to track the CD8 ؉ T cell response over a 2 year period. This longitudinal analysis showed the following. 1) Memory CD8 ؉ T cells appear to pass through an effector phase and then gradually downregulate expression of activation markers and effector molecules. 2) This effector phase was characterized by down-regulation of CD127, Bcl-2, CCR7, and CD45RA and was followed by a substantial contraction resulting in a pool of memory T cells that re-expressed CD127, Bcl-2, and CD45RA. 3) These memory cells were polyfunctional in terms of degranulation and production of the cytokines IFN-␥, TNF-␣, IL-2, and MIP-1. 4) The YF-17D-specific memory CD8 ؉ T cells had a phenotype (CCR7 ؊ CD45RA ؉ ) that is typically associated with terminally differentiated cells with limited proliferative capacity (T EMRA ). However, these cells exhibited robust proliferative potential showing that expression of CD45RA may not always associate with terminal differentiation and, in fact, may be an indicator of highly functional memory CD8 ؉ T cells generated after acute viral infections.
Generating long-lived CD8+T-cell memory: Insights from epigenetic programs
European Journal of Immunology, 2016
T cell based immunological memory has the potential to provide the host with lifelong protection against pathogen re-exposure and thus offers tremendous promise for the design of vaccines targeting chronic infections or cancer. In order to exploit this potential in the design of new vaccines it is necessary to understand how and when memory T cells acquire their poised effector potential, and moreover, how they maintain these properties during homeostatic proliferation. To gain insight into the persistent nature of memory T cell functions, investigators have turned their attention to epigenetic mechanisms. Recent efforts have revealed that many of the properties acquired among memory T cells are coupled to stable changes in DNA methylation and histone modifications. Furthermore, it has recently been reported that the delineating features among memory T cells subsets are also linked to distinct epigenetic events providing exciting new hypotheses regarding their cellular ancestry. Here we review recent studies focused on epigenetic programs acquired during effector and memory T cell differentiation and discuss how these data may shed new light on the developmental path for generating long-lived CD8 T cell memory.
Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis
The Journal of Experimental Medicine
Antigen-independent homeostasis of memory CD8 T cells is vital for sustaining long-lived T cell–mediated immunity. In this study, we report that maintenance of human memory CD8 T cell effector potential during in vitro and in vivo homeostatic proliferation is coupled to preservation of acquired DNA methylation programs. Whole-genome bisulfite sequencing of primary human naive, short-lived effector memory (T EM ), and longer-lived central memory (T CM ) and stem cell memory (T SCM ) CD8 T cells identified effector molecules with demethylated promoters and poised for expression. Effector-loci demethylation was heritably preserved during IL-7– and IL-15–mediated in vitro cell proliferation. Conversely, cytokine-driven proliferation of T CM and T SCM memory cells resulted in phenotypic conversion into T EM cells and was coupled to increased methylation of the CCR7 and Tcf7 loci. Furthermore, haploidentical donor memory CD8 T cells undergoing in vivo proliferation in lymphodepleted recip...
Human Effector and Memory CD8+ T Cell Responses to Smallpox and Yellow Fever Vaccines
Immunity, 2008
To explore the human T cell response to acute viral infection, we performed a longitudinal analysis of CD8 + T cells responding to the live yellow fever virus and smallpox vaccines-two highly successful human vaccines. Our results show that both vaccines generated a brisk primary effector CD8 + T cell response of substantial magnitude that could be readily quantitated with a simple set of four phenotypic markers. Secondly, the vaccine-induced T cell response was highly specific with minimal bystander effects. Thirdly, virus-specific CD8 + T cells passed through an obligate effector phase, contracted more than 90% and gradually differentiated into long-lived memory cells. Finally, these memory cells were highly functional and underwent a memory differentiation program distinct from that described for human CD8 + T cells specific for persistent viruses. These results provide a benchmark for CD8 + T cell responses induced by two of the most effective vaccines ever developed.
Attrition of memory CD8 T cells
Nature, 2009
Vezys et al 1 make the interesting observation that it is possible to repeatedly immunize mice in ways that allow for development of high numbers of memory CD8 T cells without depleting pre-existing memory cells specific for other pathogens. This study, which offers promise in developing potent vaccination schemes, is seemingly at odds with work published by us in the 1990's showing a loss in CD8 memory cells after a series of infections. 2,3 Vezys et al mention that we may have misinterpreted our data because we reported the putative loss of memory T cells as percent rather than total number, but here we represent the data in those studies as total cell number. limiting dilution assay data, a measure mostly of central memory cells, with 3 to 11 determinations per group, and shows determinations with intracellular cytokine and MHC-dimer assays, with 6 determinations per group. They show that losses in memory CD8 cells became statistically significant after a series of viral infections. Virus-induced losses in total body memory have also been reported by in vivo cytotoxicity assays, which monitor the ability of T cells to kill antigen-expressing targets in the host. 5 Others have reported bacteria-induced losses of T cell-dependent immunity to tumors. 6 These findings differ with the conclusions of Vezys, et al, 1 who examined loss of memory cells after infections with only a single pathogen or after a series of immunizations with vectors encoding the same antigen in a prime-boost immunization scheme.
Epigenetic Maintenance of Acquired Gene Expression Programs during Memory CD8 T Cell Homeostasis
Frontiers in Immunology, 2018
Memory CD8 T cells have a unique ability to provide lifelong immunity against pathogens containing their cognate epitope. Because of their ability to provide lifelong protection, the generation of memory T cells is now a major focus for current vaccination or adoptive cell therapy approaches to treat chronic viral infections and cancer. It is now clear that maintenance of memory CD8 T cells occurs through a process of antigen-independent homeostatic proliferation, which is regulated in part by the gamma chain cytokines IL-7 and IL-15. Here, we will describe the role of these cytokines in the survival and self-renewal of memory CD8 T cells. Further, we will describe the role of epigenetics in the maintenance of acquired functions among memory CD8 T cells during homeostatic proliferation.
Nature medicine, 2001
Emerging evidence indicates that CD8+ and CD4+ T-cell immunity is differentially regulated. Here we have delineated differences and commonalities among antiviral T-cell responses by enumeration and functional profiling of eight specific CD8+ and CD4+ T-cell populations during primary, memory and recall responses. A high degree of coordinate regulation among all specific T-cell populations stood out against an approximately 20-fold lower peak expansion and prolonged contraction phase of specific CD4+ T-cell populations. Surprisingly, although CD8+ T-cell memory was stably maintained for life, levels of specific CD4+ memory T cells gradually declined. However, this decay, which seemed to result from less efficient rescue from apoptosis, did not affect functionality of surviving virus-specific CD4+ T cells. Our results indicate that CD4+ T-cell memory might become limiting under physiological conditions and that conditions precipitating CD4+ T-cell loss might compromise protective immu...
CD8 T cell memory: it takes all kinds
Frontiers in immunology, 2012
Understanding the mechanisms that regulate the differentiation and maintenance of CD8(+) memory T cells is fundamental to the development of effective T cell-based vaccines. Memory cell differentiation is influenced by the cytokines that accompany T cell priming, the history of previous antigen encounters, and the tissue sites into which memory cells migrate. These cues combine to influence the developing CD8(+) memory pool, and recent work has revealed the importance of multiple transcription factors, metabolic molecules, and surface receptors in revealing the type of memory cell that is generated. Paired with increasingly meticulous subsetting and sorting of memory populations, we now know the CD8(+) memory pool to be phenotypically and functionally heterogeneous in nature. This includes both recirculating and tissue-resident memory populations, and cells with varying degrees of inherent longevity and protective function. These data point to the importance of tailored vaccine desi...