The Yellow Fever Virus Vaccine Induces a Broad and Polyfunctional Human Memory CD8+ T Cell Response (original) (raw)
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Origin and differentiation of human memory CD8 T cells after vaccination
Nature, 2017
The differentiation of human memory CD8 T cells is not well understood. Here we address this issue using the live yellow fever virus (YFV) vaccine, which induces long-term immunity in humans. We used in vivo deuterium labelling to mark CD8 T cells that proliferated in response to the virus and then assessed cellular turnover and longevity by quantifying deuterium dilution kinetics in YFV-specific CD8 T cells using mass spectrometry. This longitudinal analysis showed that the memory pool originates from CD8 T cells that divided extensively during the first two weeks after infection and is maintained by quiescent cells that divide less than once every year (doubling time of over 450 days). Although these long-lived YFV-specific memory CD8 T cells did not express effector molecules, their epigenetic landscape resembled that of effector CD8 T cells. This open chromatin profile at effector genes was maintained in memory CD8 T cells isolated even a decade after vaccination, indicating tha...
Tight Regulation of Memory CD8+ T Cells Limits Their Effectiveness during Sustained High Viral Load
Immunity, 2011
To design successful vaccines for chronic diseases, an understanding of memory CD8 + T cell responses to persistent antigen restimulation is critical. However, most studies comparing memory and naive cell responses have been performed only in rapidly cleared acute infections. Herein, by comparing the responses of memory and naive CD8 + T cells to acute and chronic lymphocytic choriomeningitis virus infection, we show that memory cells dominated over naive cells and were protective when present in sufficient numbers to quickly reduce infection. In contrast, when infection was not rapidly reduced, because of high antigen load or persistence, memory cells were quickly lost, unlike naive cells. This loss of memory cells was due to a block in sustaining cell proliferation, selective regulation by the inhibitory receptor 2B4, and increased reliance on CD4 + T cell help. Thus, emphasizing the importance of designing vaccines that elicit effective CD4 + T cell help and rapidly control infection.
Expression of CD8? identifies a distinct subset of effector memory CD4 + T lymphocytes
Immunology, 2006
Circulating CD4 + CD8 + T lymphocytes have been described in the peripheral blood of humans and several animal species. However, the origin and functional properties of these cells remain poorly understood. In the present study, we evaluated the frequency, phenotype and function of peripheral CD4 + CD8 + T cells in rhesus macaques. Two distinct populations of CD4 + CD8 + T cells were identified: the dominant one was CD4 hi CD8 lo and expressed the CD8aa homodimer, while the minor population was CD4 lo CD8 hi and expressed the CD8ab heterodimer. The majority of CD4 hi CD8a lo T cells exhibited an activated effector/memory phenotype (CCR5 lo CD7-CD28-HLA-DR +) and expressed relatively high levels of granzyme B. Intracellular cytokine staining assays demonstrated that the frequency of cytomegalovirus-specific T cells was enriched five-fold in CD4 hi CD8a lo T cells compared to single-positive CD4 + T cells, whereas no consistent enrichment was observed for simian immunodeficiency virus (SIV)-specific T cells. Cross-sectional studies of SIV-infected animals demonstrated that the frequency of CD4 hi CD8a lo T cells was lower in wild-type SIV-infected animals compared to uninfected controls, although prospective studies of SIV-infected animals demonstrated depletion of CD4 hi CD8a lo lymphocytes only in a subset of animals. Taken together, these data suggest that CD4 + T cells expressing CD8a represent an effector/memory subset of CD4 + T cells and that this cell population can be depleted during the course of SIV infection.
Expression of CD8? identifies a distinct subset of effector memory CD4+T lymphocytes
Immunology, 2006
Circulating CD4 + CD8 + T lymphocytes have been described in the peripheral blood of humans and several animal species. However, the origin and functional properties of these cells remain poorly understood. In the present study, we evaluated the frequency, phenotype and function of peripheral CD4 + CD8 + T cells in rhesus macaques. Two distinct populations of CD4 + CD8 + T cells were identified: the dominant one was CD4 hi CD8 lo and expressed the CD8aa homodimer, while the minor population was CD4 lo CD8 hi and expressed the CD8ab heterodimer. The majority of CD4 hi CD8a lo T cells exhibited an activated effector/memory phenotype (CCR5 lo CD7-CD28-HLA-DR +) and expressed relatively high levels of granzyme B. Intracellular cytokine staining assays demonstrated that the frequency of cytomegalovirus-specific T cells was enriched five-fold in CD4 hi CD8a lo T cells compared to single-positive CD4 + T cells, whereas no consistent enrichment was observed for simian immunodeficiency virus (SIV)-specific T cells. Cross-sectional studies of SIV-infected animals demonstrated that the frequency of CD4 hi CD8a lo T cells was lower in wild-type SIV-infected animals compared to uninfected controls, although prospective studies of SIV-infected animals demonstrated depletion of CD4 hi CD8a lo lymphocytes only in a subset of animals. Taken together, these data suggest that CD4 + T cells expressing CD8a represent an effector/memory subset of CD4 + T cells and that this cell population can be depleted during the course of SIV infection.
The Journal of …, 2001
Using HLA class I-viral epitope tetramers to monitor herpes virus-specific CD8 ؉ T cell responses in humans, we have shown that a significant fraction of responding cells revert from a CD45RO ؉ to a CD45RA ؉ state after priming. All tetramer-binding CD45RA ؉ cells, regardless of epitope specificity, expressed a phenotype LFA-1 high CCR7 low that was stable for at least 10 years in infectious mononucleosis patients and indefinitely in asymptomatic carriers. CD8 ؉ CD45RA ؉ LFA-1 high cells were not present in cord blood but in adults account for up to 50% of CD8 ؉ CD45RA ؉ cells. These CD45RA ؉ LFA-1 high cells have significantly shorter telomeres than CD45RA ؉ LFA-1 low cells, suggesting that the latter represent a naive population, while the former are memory cells. CD45RA ؉ memory cells are a stable population of noncycling cells, but on stimulation they are potent producers of IFN-␥, while naive CD8 ؉ cells produce only IL-2. The chemokine receptor profile and migratory potential of CD45RA ؉ memory cells is very similar to CD45RO ؉ cells but different to naive CD8 cells. In accord with this, CD45RA ؉ memory cells were significantly underrepresented in lymph nodes, but account for virtually all CD8 ؉ CD45RA ؉ T cells in peripheral tissues of the same individuals.
Infection History Determines the Differentiation State of Human CD8+ T-cells
Journal of virology, 2015
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...
Concurrent Generation of Effector and Central Memory CD8 T Cells during Vaccinia Virus Infection
PLoS ONE, 2008
It is generally thought that during the contraction phase of an acute anti-viral T cell reponse, the effector T cells that escape activation-induced cell death eventually differentiate into central memory T cells over the next several weeks. Here we report that antigen-specific CD8T cells with the phenotype and function of central memory cells develop concomitantly with effector T cells during vaccinia virus (vv) infection. As soon as 5 days after an intraperitoneal infection with vv, we could identify a subset of CD44 hi and CD62L + vv-specific CD8 T cells in the peritoneal exudate lymphocytes. This population constituted approximately 10% of all antigen-specific T cells and like central memory T cells, they also expressed high levels of CCR7 and IL-7R but expressed little granzyme B. Importantly, upon adoptive transfer into naïve congenic hosts, CD62L + , but not CD62L 2 CD8 T cells were able to expand and mediate a rapid recall response to a new vv challenge initiated 6 weeks after transfer, confirming that the CD62L + vv-specific CD8 T cells are bonafide memory cells. Our results are thus consistent with the branched differentiation model, where effector and memory cells develop simultaneously. These results are likely to have implications in the context of vaccine design, particularly those based on vaccinia virus recombinants.