Reverse TCR repertoire evolution toward dominant low-affinity clones during chronic CMV infection

Schober, Kilian; Voit, Florian; Grassmann, Simon; Müller, Thomas; Eggert, Joel; Jarosch, Sebastian; Weißbrich, Bianca; Hoffmann, Patrick; Borkner, Lisa; Nio, Enzo; Fanchi, Lorenzo F.; Clouser, Christopher R.; Radhakrishnan, Aditya; Mihatsch, Lorenz; Lückemeier, Philipp; Leube, Justin; Dössinger, Georg; Klein, Ludger; Neuenhahn, Michael; Oduro, Jennifer D.; Čičin‐Šain, Luka; Buchholz, Veit R.; Busch, Dirk H.

doi:10.1038/s41590-020-0628-2

Cited by 94 publications

(112 citation statements)

References 58 publications

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“…After an observation time of 72 wks, when mice had reached senescence, a secondary contraction was observed, during which primarily the pool of high avidity cells collapsed. Interestingly, Schober and colleagues [67] discussed a model predicting such a preferential loss of high avidity T-cell clones at late stages following MI, due to 'proliferative senescence', and evidence in support of this model has been provided just recently [55]. Our data are consistent with this finding and indicate that loss of high avidity cells is not just the fate of individual clones but indeed applies also to polyclonal populations and to different epitopes.…”

Section: Discussionsupporting

confidence: 84%

“…One may wonder why the response rate was low in the high avidity CTLL compared to the low avidity CTLL. An explanation may be that high avidity interaction and the resulting extensive signaling lead to exhaustion preferentially of high avidity cells, as shown recently by Schober and colleagues [55] and discussed below for selective loss of high avidity clones in vivo.…”

Section: Functional Avidity Of Cd8 T Cells Is Decisive For Overcomingmentioning

confidence: 86%

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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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Section: Discussionsupporting

confidence: 84%

Section: Functional Avidity Of Cd8 T Cells Is Decisive For Overcomingmentioning

confidence: 86%

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

et al. 2020

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“…This mechanism has now been defined as "memory inflation" and documented over the course of several viral infections (122,123). In a recent study, Schober and colleagues studied TCR repertoire evolution in the context of latent CMV infection and found that, although high-affinity TCRs dominated T cell responses at early times after infection, low affinity TCRs emerged over time, owing to cellular differentiation and senescence (and not exhaustion) of high affinity ones (124). In a recent publication, Poschke and coauthors exploited TCR deep sequencing to characterize TILs before and after in vitro culture and found that dominant T cell clones were lost during TIL culture because of poor expansion potential, in favor of less represented ones (125).…”

Section: Tcr Affinity/aviditymentioning

confidence: 99%

To Remember or to Forget: The Role of Good and Bad Memories in Adoptive T Cell Therapy for Tumors

Mondino

Manzo

2020

Front. Immunol.

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The generation of immunological memory is a hallmark of adaptive immunity by which the immune system "remembers" a previous encounter with an antigen expressed by pathogens, tumors, or normal tissues; and, upon secondary encounters, mounts faster and more effective recall responses. The establishment of T cell memory is influenced by both cell-intrinsic and cell-extrinsic factors, including genetic, epigenetic and environmental triggers. Our current knowledge of the mechanisms involved in memory T cell differentiation has instructed new opportunities to engineer T cells with enhanced anti-tumor activity. The development of adoptive T cell therapy has emerged as a powerful approach to cure a subset of patients with advanced cancers. Efficacy of this approach often requires long-term persistence of transferred T cell products, which can vary according to their origin and manufacturing conditions. Host preconditioning and post-transfer supporting strategies have shown to promote their engraftment and survival by limiting the competition with a hostile tumor microenvironment and between pre-existing immune cell subsets. Although in the general view pre-existing memory can confer a selective advantage to adoptive T cell therapy, here we propose that also "bad memories"-in the form of antigen-experienced T cell subsets-co-evolve with consequences on newly transferred lymphocytes. In this review, we will first provide an overview of selected features of memory T cell subsets and, then, discuss their putative implications for adoptive T cell therapy.

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“…In contrast, some other findings support the view that clonal selection of low-avidity clones through loss of high avidity clones (effect 2) occurs in both humans and mice (Schober et al, 2020) ing study, which proposed that repetitive stimulation due to virus reactivation could lead to loss of high avidity clones (Davenport et al, 2002). Ex vivo analyses showed that during primary EBV infection, high-affinity EBV-specific TCRs were selected, while 1 year later a decrease in affinity was observed.…”

Section: F I G U R Ementioning

confidence: 73%

How age and infection history shape the antigen‐specific CD8⁺ T‐cell repertoire: Implications for vaccination strategies in older adults

2020

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Cytotoxic CD8 + T cells are important in the clearance of virus-infected cells and are therefore of interest for the development of vaccination strategies against infectious diseases. An important correlate of protection against infectious diseases is the recruitment of T cells carrying high-affinity antigen-specific T-cell receptors (TCRs) (Tscharke et al., 2015). The diversity of the recruited T-cell repertoire is also directly linked to disease outcome (Price et al., 2004, 2009), and narrow T-cell repertoires are associated with more frequent occurrence of viral escape (Cornberg et al., 2006). Higher TCR diversity has been suggested to be important for a protective immune response, as it increases the chance of both high avidity clones as well as cross-reactive clones, able to recognize antigen variants, to be present in the responding repertoire (Nikolich-Zugich et al., 2004; Turner et al., 2009). Diminished CD8 + T-cell responses to new infections and vaccination in older adults are thought to be due to a combination of decreased numbers and functional capacity, among which the priming capacity, of naive T cells with age (Briceno et al., 2016). Another important role is assigned to a decline in the diversity of the T-cell repertoire with age (Nikolich-Zugich, 2008). Although estimating

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Reverse TCR repertoire evolution toward dominant low-affinity clones during chronic CMV infection

Cited by 94 publications

References 58 publications

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

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

To Remember or to Forget: The Role of Good and Bad Memories in Adoptive T Cell Therapy for Tumors

How age and infection history shape the antigen‐specific CD8⁺ T‐cell repertoire: Implications for vaccination strategies in older adults

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Reverse TCR repertoire evolution toward dominant low-affinity clones during chronic CMV infection

Cited by 94 publications

References 58 publications

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

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

To Remember or to Forget: The Role of Good and Bad Memories in Adoptive T Cell Therapy for Tumors

How age and infection history shape the antigen‐specific CD8+ T‐cell repertoire: Implications for vaccination strategies in older adults

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Product

Resources

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How age and infection history shape the antigen‐specific CD8⁺ T‐cell repertoire: Implications for vaccination strategies in older adults