Early precursor T cells establish and propagate T cell exhaustion in chronic infection

Utzschneider, Daniel T.; Gabriel, Sarah S.; Chisanga, David; Gloury, Renee; Gubser, Patrick; Vasanthakumar, Ajithkumar; Shi, Wei; Kallies, Axel

doi:10.1038/s41590-020-0760-z

Cited by 200 publications

(207 citation statements)

References 61 publications

Supporting

Mentioning

187

Contrasting

Order By: Relevance

“…Importantly, we found that our approach, besides generating terminally differentiated effector cells, strongly reinforced exhausted CD8 1 T cells. Recent studies have demonstrated that exhausted T cells are phenotypically and functionally heterogeneous immune cells (13,14,46). Interestingly, while it has been shown that PD-1 hi CD8 1 T cells do not respond to PD-1-targeted therapy, we found GzmB expression to be highly upregulated in a distinct PD-1 hi population of FV-specific CD8 1 T cells after combination therapy, but not after therapeutic vaccination or PD-L1 blockade alone.…”

Section: Discussioncontrasting

confidence: 61%

A Combination of Anti-PD-L1 Treatment and Therapeutic Vaccination Facilitates Improved Retroviral Clearance via Reactivation of Highly Exhausted T Cells

Knuschke

Kollenda²,

Wenzek

et al. 2021

mBio

View full text Add to dashboard Cite

PD-1-targeted therapies have shown modest antiviral effects in preclinical models of chronic viral infection. Thus, novel therapy protocols are necessary to enhance T cell immunity and viral control to overcome T cell dysfunction and immunosuppression. Here, we demonstrate that nanoparticle-based therapeutic vaccination improved PD-1-targeted therapy during chronic infection with Friend retrovirus (FV). Prevention of inhibitory signals by blocking PD-L1 in combination with therapeutic vaccination with nanoparticles containing the microbial compound CpG and a CD8+ T cell Gag epitope peptide synergistically enhanced functional virus-specific CD8+ T cell responses and improved viral clearance. We characterized the CD8+ T cell populations that were affected by this combination therapy, demonstrating that new effector cells were generated and that exhausted CD8+ T cells were reactivated at the same time. While CD8+ T cells with high PD-1 (PD-1hi) expression turned into a large population of granzyme B-expressing CD8+ T cells after combination therapy, CXCR5-expressing follicular cytotoxic CD8+ T cells also expanded to a high degree. Thus, our study describes a very efficient approach to enhance virus control and may help us to understand the mechanisms of combination immunotherapy reactivating CD8+ T cell immunity. A better understanding of CD8+ T cell immunity during combination therapy will be important for developing efficient checkpoint therapies against chronic viral infections and cancer. IMPORTANCE Despite significant efforts, vaccines are not yet available for every infectious pathogen, and the search for a protective approach to prevent the establishment of chronic infections, i.e., with HIV, continues. Immune checkpoint therapies targeting inhibitory receptors, such as PD-1, have shown impressive results against solid tumors. However, immune checkpoint therapies have not yet been licensed to treat chronic viral infections, since a blockade of inhibitory receptors alone provides only limited benefit, as demonstrated in preclinical models of chronic viral infection. Thus, there is a high interest in the development of potent combination immunotherapies. Here, we tested whether the combination of a PD-L1 blockade and therapeutic vaccination with functionalized nanoparticles is a potent therapy during chronic Friend retrovirus infection. We demonstrate that the combination therapy induced a synergistic reinvigoration of the exhausted virus-specific CD8+ T cell immunity. Taken together, our results provide further information on how to improve PD-1-targeted therapies during chronic viral infection and cancer.

show abstract

Section: Discussioncontrasting

confidence: 61%

A Combination of Anti-PD-L1 Treatment and Therapeutic Vaccination Facilitates Improved Retroviral Clearance via Reactivation of Highly Exhausted T Cells

Knuschke

Kollenda²,

Wenzek

et al. 2021

mBio

View full text Add to dashboard Cite

show abstract

“…Alternatively, a more recent study showed that Tcf1 + Tim-3 − and Tcf1 − Tim-3 + T cell populations develop early in both acute and chronic viral infections with the Tcf1 + population giving rise to the pool of exhausted T cells. 90 Jadhav et al examined the chromatin accessibility of these PD-1 + CXCR5 + Tim-3 − stem-like cells against the PD-1 + CXCR5 + Tim-3 + exhausted T cell populations. They found that the stem-like population was enriched for TF motifs from the HMG, RHD, and TBX families, while the exhausted population was enriched for ETS and Runx motifs, 91…”

Section: Impac T Of Epi G Ene Ti C S On T Cell Ther Apeuti C Smentioning

confidence: 99%

Epigenetic regulation of T cell adaptive immunity

Frias

Boi

et al. 2021

Immunological Reviews

View full text Add to dashboard Cite

show abstract

“…Consistent with this, bulk gene expression in FACS-purified subsets that are "T EFF -like" based on being KLRG1 hi or Id2 hi at early times after infection is more enriched with gene expression from mature TE cells, whereas those that are more "T MEM -like" based on being KLRG1 lo , or Id3 hi , are more enriched with gene expression characteristic of T MEM or MP cells. 49,53,64,70 However, discerning the cells that are actually "differentiated" at early times on the basis of only a handful of surface receptors or reporter genes is likely limited, because of transcriptomic variation between single cells, 69 and gene expression patterns that do not stabilize until later. For example, gene expression on day 5 after infection is more similar between KRLG1 hi and KLRG1 lo cells than it is between either subset and naive cells, or between either subset and mature EE, TE, or MP phenotypic cells on day 8 post-LCMV Arm infection.…”

Section: Heterogeneous Gene Expression In Activated Cd8 T Cells Leamentioning

confidence: 99%

Runx proteins and transcriptional mechanisms that govern memory CD8 T cell development

Pipkin

2021

Immunological Reviews

View full text Add to dashboard Cite

Adaptive immunity to intracellular pathogens and tumors is mediated by antigenexperienced CD8 T cells. Individual naive CD8 T cells have the potential to differentiate into a diverse array of antigen-experienced subsets that exhibit distinct effector functions, life spans, anatomic positioning, and potential for regenerating an entirely new immune response during iterative pathogenic exposures. The developmental process by which activated naive cells undergo diversification involves regulation of chromatin structure and transcription but is not entirely understood. This review examines how alterations in chromatin structure, transcription factor binding, extracellular signals, and single-cell gene expression explain the differential development of distinct effector (T EFF) and memory (T MEM) CD8 T cell subsets. Special emphasis is placed on how Runx proteins function with additional transcription factors to pioneer changes in chromatin accessibility and drive transcriptional programs that establish the core attributes of cytotoxic T lymphocytes, subdivide circulating and non-circulating T MEM cell subsets, and govern terminal differentiation. The discussion integrates the roles of specific cytokine signals, transcriptional circuits and how regulation of individual nucleosomes and RNA polymerase II activity can contribute to the process of differentiation. A model that integrates many of these features is discussed to conceptualize how activated CD8 T cells arrive at their fates.

show abstract

Early precursor T cells establish and propagate T cell exhaustion in chronic infection

Cited by 200 publications

References 61 publications

A Combination of Anti-PD-L1 Treatment and Therapeutic Vaccination Facilitates Improved Retroviral Clearance via Reactivation of Highly Exhausted T Cells

A Combination of Anti-PD-L1 Treatment and Therapeutic Vaccination Facilitates Improved Retroviral Clearance via Reactivation of Highly Exhausted T Cells

Epigenetic regulation of T cell adaptive immunity

Runx proteins and transcriptional mechanisms that govern memory CD8 T cell development

Contact Info

Product

Resources

About