Type 1 conventional dendritic cells maintain and guide the differentiation of precursors of exhausted T cells in distinct cellular niches

Dähling, Sabrina; Mansilla, Ana Maria; Knöpper, Konrad; Grafen, Anika; Utzschneider, Daniel T.; Ugur, Milas; Whitney, Paul G.; Bachem, Annabell; Arampatzi, Panagiota; Imdahl, Fabian; Kaisho, Tsuneyasu; Zehn, Dietmar; Klauschen, Frederick; Garbi, Natalio; Kallies, Axel; Gasteiger, Georg; Bedoui, Sammy; Kastenmüller, Wolfgang

doi:10.1016/j.immuni.2022.03.006

Cited by 58 publications

(60 citation statements)

References 62 publications

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“…But, in addition to activation molecules, mregDC also express the highest levels of PD-L1 and PD-L2 among DC, and it is possible that mregDC-mediated PD-L1/PD-1 activation on progenitor CD8 T cells limits their terminal differentiation and permits their maintenance in a progenitor state in these discrete cellular niches. These results align with prior studies showing that tumors enriched in MHC-II + cells and CD8 T cells are less likely to relapse after surgery and that proximity to CD11c + MHC-II + cells may enable CD8 T cells to retain a polyfunctional, progenitor state (Dähling et al, 2022;Duraiswamy et al, 2021;Jansen et al, 2019).…”

Section: Discussionsupporting

confidence: 90%

“…Using receptor-ligand mapping ( Figure 4B ), we analyzed the expression of candidate molecules that might promote interactions between mregDC, CXCL13 + Th, and PD-1 hi CD8 T cells. We found that among cDC, mregDC expressed the highest levels of the CD4 T cell ligands ( CCL22 , CCL17 ); the naive and central memory T cell ligand CCL19 , co-stimulatory molecules ( CD80 , CD86 , PVR , PVRL2 , CD40 ); cytokines that modulate T cells, such as IL12B , which is known to promote Th1 cell differentiation (Garris et al, 2018; Martínez-López et al, 2015; Schurich et al, 2013), and IL15 , which has been shown to promote CD8 and NK cell survival; and regulatory molecules CD274 (encoding PD-L1) and PDCD1LG2 (encoding PD-L2), which we hypothesize may help protect progenitor CD8 T cells from terminal exhaustion (Dähling et al, 2022).…”

Section: Resultsmentioning

confidence: 99%

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Intratumoral mregDC and CXCL13 T helper niches enable local differentiation of CD8 T cells following PD-1 blockade

Magen

Hamon

Fiaschi

et al. 2022

Preprint

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Here, we leveraged a large neoadjuvant PD-1 blockade trial in patients with hepatocellular carcinoma (HCC) to search for correlates of response to immune checkpoint blockade (ICB) within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13+ CH25H+ IL-21+ PD-1+ CD4 T helper cells (CXCL13+ Th) and Granzyme K+ PD-1+ effector-like CD8 T cells, whereas terminally exhausted CD39hi TOXhi PD-1hi CD8 T cells dominated in non-responders. Strikingly, most T cell receptor (TCR) clones that expanded post-treatment were found in pre-treatment biopsies. Notably, PD-1+ TCF-1+ progenitor-like CD8 T cells were present in tumors of responders and non-responders and shared clones mainly with effector-like cells in responders or terminally differentiated cells in non-responders, suggesting that local CD8 T cell differentiation occurs upon ICB. We found that these progenitor CD8 T cells interact with CXCL13+ Th cells within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or "mregDC". Receptor-ligand analysis revealed unique interactions within these triads that may promote the differentiation of progenitor CD8 T cells into effector-like cells upon ICB. These results suggest that discrete intratumoral niches that include mregDC and CXCL13+ Th cells control the differentiation of tumor-specific progenitor CD8 T cell clones in patients treated with ICB.

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Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Intratumoral mregDC and CXCL13 T helper niches enable local differentiation of CD8 T cells following PD-1 blockade

Magen

Hamon

Fiaschi

et al. 2022

Preprint

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“…1 | Isolation of polyclonal exhausted T cells for scRNA-seq and phenotypic characterization of CD62L + T PEX cells in chronic infection. (a, b) CD4 + T cell-depleted naive mice were infected with LCMV-Cl13, treated with or without anti-PD-L1, and exhausted PD-1 + TIM-3 lo T cells were sorted at >day 30 post-infection as described 19…”

Section: Bulk Rna Extraction Sequencing and Analysismentioning

confidence: 99%

“…To identify factors that promote the self-renewal and multipotency of T PEX cells, we performed single-cell RNA sequencing (scRNA-seq) of T PEX -cell-enriched (PD-1 + TIM-3 − ) CD8 + T cells sorted at 30 days post-infection (dpi) from mice chronically infected with lymphocytic choriomeningitis virus (LCMV) clone-13 (Cl13). Combined analysis of our data and publicly available scRNA-seq datasets 11 , 19 (Fig. 1a and Extended Data Fig.…”

Section: Cd62l + T Pex Cells Ha...mentioning

confidence: 99%

MYB orchestrates T cell exhaustion and response to checkpoint inhibition

Tsui

Kretschmer

Rapelius

et al. 2022

Nature

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106

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CD8+ T cells that respond to chronic viral infections or cancer are characterized by the expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and by the impaired production of cytokines. This state of restrained functionality—which is referred to as T cell exhaustion1,2—is maintained by precursors of exhausted T (TPEX) cells that express the transcription factor T cell factor 1 (TCF1), self-renew and give rise to TCF1− exhausted effector T cells3–6. Here we show that the long-term proliferative potential, multipotency and repopulation capacity of exhausted T cells during chronic infection are selectively preserved in a small population of transcriptionally distinct CD62L+ TPEX cells. The transcription factor MYB is not only essential for the development of CD62L+ TPEX cells and maintenance of the antiviral CD8+ T cell response, but also induces functional exhaustion and thereby prevents lethal immunopathology. Furthermore, the proliferative burst in response to PD-1 checkpoint inhibition originates exclusively from CD62L+ TPEX cells and depends on MYB. Our findings identify CD62L+ TPEX cells as a stem-like population that is central to the maintenance of long-term antiviral immunity and responsiveness to immunotherapy. Moreover, they show that MYB is a transcriptional orchestrator of two fundamental aspects of exhausted T cell responses: the downregulation of effector function and the long-term preservation of self-renewal capacity.

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“…Moreover, the stem-like TCF-1 + cells generated were able to differentiate into effector CD8 + T cells to elicit anti-tumour responses (78). Similarly, the duration of antigen presentation by specific dendritic populations in the draining lymph node and spleen may help augment and/or maintain the reservoir of TCF-1 + CD8 + T cells required for optimal immunity during chronic antigen exposure (79)(80)(81). Such reports suggest that routes and types of immunizations can elicit responses that facilitate the development of successful tumor vaccines to overcome limitations of exhaustion.…”

Section: Not All Roads Lead To Rome -Routes To Prevent Exhaustionmentioning

confidence: 99%

The Road Less Taken: Less Appreciated Pathways for Manipulating CD8+ T Cell Exhaustion

2022

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Exhausted CD8+ T (Tex) cells are a distinct cell population that arise during persistent antigen exposure in the context of chronic infections and cancers. Although characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression and distinct transcriptional and epigenetic programs, Tex cells are heterogeneous. Among these, a self-renewing TCF-1+ Tex population, having unique characteristics and the ability to respond to immune-checkpoint blockade, gives rise to TCF-1- terminally Tex cells. These TCF-1+ cells have stem cell-like properties similar to memory T cell populations, but the signals that regulate the developmental pathways and relationships among exhausted cell populations are still unclear. Here, we review our current understanding of Tex cell biology, and discuss some less appreciated molecules and pathways affecting T cell exhaustion. We highlight two co-stimulatory receptors, CD226 and CD137, and their role in inducing or restraining T cell exhaustion, as well as signaling pathways that may be amenable to pharmacological inhibition with a focus on Phosphoinositide-3 Kinase and IL-2 partial agonists. Finally, we discuss novel methods that may increase TCF-1+ populations and therefore improve immunotherapy responsiveness. Understanding features of and pathways to exhaustion has important implications for the success of immunotherapy, including checkpoint blockade and adoptive T-cell transfer therapies.

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Type 1 conventional dendritic cells maintain and guide the differentiation of precursors of exhausted T cells in distinct cellular niches

Cited by 58 publications

References 62 publications

Intratumoral mregDC and CXCL13 T helper niches enable local differentiation of CD8 T cells following PD-1 blockade

Intratumoral mregDC and CXCL13 T helper niches enable local differentiation of CD8 T cells following PD-1 blockade

MYB orchestrates T cell exhaustion and response to checkpoint inhibition

The Road Less Taken: Less Appreciated Pathways for Manipulating CD8+ T Cell Exhaustion

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