Fuel and brake of memory T cell inflation

Welten, Suzanne P. M.; Baumann, Nicolas S.; Oxenius, Annette

doi:10.1007/s00430-019-00587-9

Cited by 31 publications

(28 citation statements)

References 94 publications

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“…In models of acute infection it has been shown that KLRG1 - cells have a higher probability to feed into the memory pool [34], making it likely that these cells also give rise to the T CM cells in MCMV infection. Thus, the number of central memory T cells that is able to sense viral reactivation events is one feature that drives memory inflation, but more factors promote T cell inflation as well [57]. This for instance includes the amount of latent viral genomes present in non-hematopoietic cells that is also related to the viral inoculum dose and the amount of latent viral genomes in the spleen determined by the route of infection and by immune evasion strategies [15, 36, 58, 59].…”

Section: Discussionmentioning

confidence: 99%

Early primed KLRG1- CMV-specific T cells determine the size of the inflationary T cell pool

et al. 2019

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Memory T cell inflation is a process in which a subset of cytomegalovirus (CMV) specific CD8 T cells continuously expands mainly during latent infection and establishes a large and stable population of effector memory cells in peripheral tissues. Here we set out to identify in vivo parameters that promote and limit CD8 T cell inflation in the context of MCMV infection. We found that the inflationary T cell pool comprised mainly high avidity CD8 T cells, outcompeting lower avidity CD8 T cells. Furthermore, the size of the inflationary T cell pool was not restricted by the availability of specific tissue niches, but it was directly related to the number of virus-specific CD8 T cells that were activated during priming. In particular, the amount of early-primed KLRG1 - cells and the number of inflationary cells with a central memory phenotype were a critical determinant for the overall magnitude of the inflationary T cell pool. Inflationary memory CD8 T cells provided protection from a Vaccinia virus challenge and this protection directly correlated with the size of the inflationary memory T cell pool in peripheral tissues. These results highlight the remarkable protective potential of inflationary CD8 T cells that can be harnessed for CMV-based T cell vaccine approaches.

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Section: Discussionmentioning

confidence: 99%

Early primed KLRG1- CMV-specific T cells determine the size of the inflationary T cell pool

et al. 2019

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“…After clearance of productive infection, transient contraction of the viral-epitope specific pool of CD8 + T cells is followed by pool expansion selectively for certain viral epitopes during nonproductive, latent infection (2)(3)(4)(5)(6). This phenomenon is known as "memory inflation" (MI) (for reviews, see (7)(8)(9)(10)(11)). MI has prompted the promising idea to use CMVs as vaccine vectors by replacing endogenous MI-driving epitopes with epitopes of unrelated pathogens or tumors to generate enduring and selfenhancing immunological memory [ (12)(13)(14)(15)(16), reviewed in (17)(18)(19)].…”

Section: Introductionmentioning

confidence: 99%

Stochastic Episodes of Latent Cytomegalovirus Transcription Drive CD8 T-Cell “Memory Inflation” and Avoid Immune Evasion

et al. 2021

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Acute infection with murine cytomegalovirus (mCMV) is controlled by CD8+ T cells and develops into a state of latent infection, referred to as latency, which is defined by lifelong maintenance of viral genomes but absence of infectious virus in latently infected cell types. Latency is associated with an increase in numbers of viral epitope-specific CD8+ T cells over time, a phenomenon known as “memory inflation” (MI). The “inflationary” subset of CD8+ T cells has been phenotyped as KLRG1+CD62L- effector-memory T cells (iTEM). It is agreed upon that proliferation of iTEM requires repeated episodes of antigen presentation, which implies that antigen-encoding viral genes must be transcribed during latency. Evidence for this has been provided previously for the genes encoding the MI-driving antigenic peptides IE1-YPHFMPTNL and m164-AGPPRYSRI of mCMV in the H-2d haplotype. There exist two competing hypotheses for explaining MI-driving viral transcription. The “reactivation hypothesis” proposes frequent events of productive virus reactivation from latency. Reactivation involves a coordinated gene expression cascade from immediate-early (IE) to early (E) and late phase (L) transcripts, eventually leading to assembly and release of infectious virus. In contrast, the “stochastic transcription hypothesis” proposes that viral genes become transiently de-silenced in latent viral genomes in a stochastic fashion, not following the canonical IE-E-L temporal cascade of reactivation. The reactivation hypothesis, however, is incompatible with the finding that productive virus reactivation is exceedingly rare in immunocompetent mice and observed only under conditions of compromised immunity. In addition, the reactivation hypothesis fails to explain why immune evasion genes, which are regularly expressed during reactivation in the same cells in which epitope-encoding genes are expressed, do not prevent antigen presentation and thus MI. Here we show that IE, E, and L genes are transcribed during latency, though stochastically, not following the IE-E-L temporal cascade. Importantly, transcripts that encode MI-driving antigenic peptides rarely coincide with those that encode immune evasion proteins. As immune evasion can operate only in cis, that is, in a cell that simultaneously expresses antigenic peptides, the stochastic transcription hypothesis explains why immune evasion is not operative in latently infected cells and, therefore, does not interfere with MI.

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“…A prominent feature of the immune response to mCMV is 'memory inflation' (MI). In essence, it was found that the acute immune response is followed by a contraction phase, during which numbers of epitope-specific CD8 T cells decline before frequencies of cells specific for certain epitopes increase steadily over time [19][20][21][22][23][24]. The epitope-selectivity of MI, distinguishing 'MI-driving' and 'MI-neutral' epitopes, is still under investigation.…”

Section: Introductionmentioning

confidence: 99%

Revisiting CD8 T-cell ‘Memory Inflation’: New Insights with Implications for Cytomegaloviruses as Vaccine Vectors

et al. 2020

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Murine models of cytomegalovirus (CMV) infection have revealed an exceptional kinetics of the immune response. After resolution of productive infection, transient contraction of the viral epitope-specific CD8 T-cell pool was found to be followed by a pool expansion specific for certain viral epitopes during non-productive ‘latent’ infection. This phenomenon, known as ‘memory inflation’ (MI), was found to be based on inflationary KLRG1+CD62L− effector-memory T cells (iTEM) that depend on repetitive restimulation. MI gained substantial interest for employing CMV as vaccine vector by replacing MI-driving CMV epitopes with foreign epitopes for generating high numbers of protective memory cells specific for unrelated pathogens. The concept of an MI-driving CMV vector is questioned by human studies disputing MI in humans. A bias towards MI in experimental models may have resulted from systemic infection. We have here studied local murine CMV infection as a route that is more closely matching routine human vaccine application. Notably, KLRG1−CD62L+ central memory T cells (TCM) and conventional KLRG1−CD62L− effector memory T cells (cTEM) were found to expand, associated with ‘avidity maturation’, whereas the pool size of iTEM steadily declined over time. The establishment of high avidity CD8 T-cell central memory encourages one to pursue the concept of CMV vector-based vaccines.

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Fuel and brake of memory T cell inflation

Cited by 31 publications

References 94 publications

Early primed KLRG1- CMV-specific T cells determine the size of the inflationary T cell pool

Early primed KLRG1- CMV-specific T cells determine the size of the inflationary T cell pool

Stochastic Episodes of Latent Cytomegalovirus Transcription Drive CD8 T-Cell “Memory Inflation” and Avoid Immune Evasion

Revisiting CD8 T-cell ‘Memory Inflation’: New Insights with Implications for Cytomegaloviruses as Vaccine Vectors

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