Helpless Priming Sends CD8+ T Cells on the Road to Exhaustion

Busselaar, Julia; Tian, Sun; Eenennaam, Hans van; Borst, Jannie

doi:10.3389/fimmu.2020.592569

Cited by 36 publications

(30 citation statements)

References 102 publications

(186 reference statements)

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“…One hypothesis is that antigen persistence during chronic infection leads to persistent TCR engagement and exhaustion, supported by the finding that the transcription factors downstream of TCR signaling—including IRF4, NFAT, Nr4a1, Nr4a2, and Nr4a3—enhance exhaustion ( Chen et al, 2019a ; Man et al, 2017 ; Martinez et al, 2015 ). Alternatively, suboptimal priming of CD8 T cells in the absence of CD4 helps favor the formation of exhausted progenitors rather than effector cells ( Busselaar et al, 2020 ; Kanev et al, 2019 ; Snell et al, 2018 ). In our experimental model, WT and MHCII KO mice differed in lung CFUs and inhibitory receptor expression by 4 wpi.…”

Section: Discussionmentioning

confidence: 99%

CD4 T cell help prevents CD8 T cell exhaustion and promotes control of Mycobacterium tuberculosis infection

et al. 2021

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CD4 T cell help prevents CD8 T cell exhaustion and promotes control of Mycobacterium tuberculosis infectionGraphical abstract Highlights d CD4 T cell help promotes CD8 T cell effector functions and prevents exhaustion d Synergy between CD4 and CD8 T cells promotes survival during murine tuberculosis d Helped, but not helpless, CD8 T cells restrict intracellular mycobacterial growth d Protection mediated by CD8 T cells

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Section: Discussionmentioning

confidence: 99%

CD4 T cell help prevents CD8 T cell exhaustion and promotes control of Mycobacterium tuberculosis infection

et al. 2021

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“…Chronic high-dose (neo)-antigen stimulation in later stages of cancer development and progression will lead to the development of progenitor-exhausted and, ultimately, terminally exhausted T cells, marked by progressively higher PD-1 expression levels and the co-expression of other immune checkpoints, like LAG3, TIM3, and TIGIT. Typical markers for the different stages of dysfunction/exhaustion are listed ( 25 – 27 ). Whereas progenitor exhausted T cells can be rescued by immune checkpoint blockade, terminal exhaustion is an irreversible state due to epigenetic programming.…”

Section: Immune Suppression Of Dendritic Cells In Tdln: Early Immune mentioning

confidence: 99%

Immunotherapy Goes Local: The Central Role of Lymph Nodes in Driving Tumor Infiltration and Efficacy

et al. 2021

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Immune checkpoint blockade (ICB) has changed the therapeutic landscape of oncology but its impact is limited by primary or secondary resistance. ICB resistance has been related to a lack of T cells infiltrating into the tumor. Strategies to overcome this hurdle have so far focused on the tumor microenvironment, but have mostly overlooked the role of tumor-draining lymph nodes (TDLN). Whereas for CTLA-4 blockade TDLN have long since been implicated due to its perceived mechanism-of-action involving T cell priming, only recently has evidence been emerging showing TDLN to be vital for the efficacy of PD-1 blockade as well. TDLN are targeted by developing tumors to create an immune suppressed pre-metastatic niche which can lead to priming of dysfunctional antitumor T cells. In this review, we will discuss the evidence that therapeutic targeting of TDLN may ensure sufficient antitumor T cell activation and subsequent tumor infiltration to facilitate effective ICB. Indeed, waves of tumor-specific, proliferating stem cell-like, or progenitor exhausted T cells, either newly primed or reinvigorated in TDLN, are vital for PD-1 blockade efficacy. Both tumor-derived migratory dendritic cell (DC) subsets and DC subsets residing in TDLN, and an interplay between them, have been implicated in the induction of these T cells, their imprinting for homing and subsequent tumor control. We propose that therapeutic approaches, involving local delivery of immune modulatory agents for optimal access to TDLN, aimed at overcoming hampered DC activation, will enable ICB by promoting T cell recruitment to the tumor, both in early and in advanced stages of cancer.

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“…CD4 T-cells are strongly implicated in the development of antitumor responses (Table 1), as they can enhance tumoricidal activity of other antitumor effector cells, such as CD8 T-cells and macrophages (6,15,16). Some CD4 subsets, particularly Th2 and T regs , are known to negatively affect the antitumor response by decreasing antigen presentation and dampening T-cell effector functions, respectively.…”

Section: Introductionmentioning

confidence: 99%

CD4 T-Cell Exhaustion: Does It Exist and What Are Its Roles in Cancer?

Miggelbrink

Jackson

Lorrey

et al. 2021

Clinical Cancer Research

139

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In chronic infections and in cancer, persistent antigen stimulation under suboptimal conditions can lead to the induction of T-cell exhaustion. Exhausted T cells are characterized by an increased expression of inhibitory markers and a progressive and hierarchical loss of function. Although cancer-induced exhaustion in CD8 T cells has been well-characterized and identified as a therapeutic target (i.e., via checkpoint inhibition), in-depth analyses of exhaustion in other immune cell types, including CD4 T cells, is wanting. While perhaps attributable to the contextual discovery of exhaustion amidst chronic viral infection, the lack of thorough inquiry into CD4 T-cell exhaustion is particularly surprising given their important role in orchestrating immune responses through T-helper and direct cytotoxic functions. Current work suggests that CD4 T-cell exhaustion may indeed be prevalent, and as CD4 T cells have been implicated in various disease pathologies, such exhaustion is likely to be clinically relevant. Defining phenotypic exhaustion in the various CD4 T-cell subsets and how it influences immune responses and disease severity will be crucial to understanding collective immune dysfunction in a variety of pathologies. In this review, we will discuss mechanistic and clinical evidence for CD4 T-cell exhaustion in cancer. Further insight into the derivation and manifestation of exhaustive processes in CD4 T cells could reveal novel therapeutic targets to abrogate CD4 T-cell exhaustion in cancer and induce a robust antitumor immune response.

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Helpless Priming Sends CD8+ T Cells on the Road to Exhaustion

Cited by 36 publications

References 102 publications

CD4 T cell help prevents CD8 T cell exhaustion and promotes control of Mycobacterium tuberculosis infection

CD4 T cell help prevents CD8 T cell exhaustion and promotes control of Mycobacterium tuberculosis infection

Immunotherapy Goes Local: The Central Role of Lymph Nodes in Driving Tumor Infiltration and Efficacy

CD4 T-Cell Exhaustion: Does It Exist and What Are Its Roles in Cancer?

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