CD4+ T Cell Help Confers a Cytotoxic T Cell Effector Program Including Coinhibitory Receptor Downregulation and Increased Tissue Invasiveness

Ahrends, Tomasz; Spanjaard, Aldo; Pilzecker, Bas; Bąbała, Nikolina; Bovens, Astrid; Xiao, Yanling; Jacobs, Heinz; Borst, Jannie

doi:10.1016/j.immuni.2017.10.009

Cited by 316 publications

(368 citation statements)

References 40 publications

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“…2A). It has been demonstrated that the inclusion of “helper” epitopes in therapeutic cancer vaccines improves the antitumor response by increasing the expansion of CD8 + T cells, as well as reducing their expression of coinhibitory receptors and increasing their migratory potential 77 …”

Section: Help In Therapeutic Contextmentioning

confidence: 99%

Harnessing neoantigen specific CD4 T cells for cancer immunotherapy

Brightman

Naradikian

Miller

et al. 2020

Journal of Leukocyte Biology

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The goal of precision immunotherapy is to direct a patient's T cell response against the immunogenic mutations expressed on their tumors. Most immunotherapy approaches to‐date have focused on MHC class I‐restricted peptide epitopes by which cytotoxic CD8+ T lymphocytes (CTL) can directly recognize tumor cells. This strategy largely overlooks the critical role of MHC class II‐restricted CD4+ T cells as both positive regulators of CTL and other effector cell types, and as direct effectors of antitumor immunity. In this review, we will discuss the role of neoantigen specific CD4+ T cells in cancer immunotherapy and how existing treatment modalities may be leveraged to engage this important T cell subset.

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Section: Help In Therapeutic Contextmentioning

confidence: 99%

Harnessing neoantigen specific CD4 T cells for cancer immunotherapy

Brightman

Naradikian

Miller

et al. 2020

Journal of Leukocyte Biology

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“…We were intrigued by earlier findings that extracellular ISG15 may act as an adjuvant to support the CTL response (34). We aimed to corroborate this and to understand the mechanistic basis, making use of a versatile therapeutic DNA vaccination model in mice (37) that we have well characterized previously (38,41,42). In this model, pDNA is applied on the depilated skin and injected into the epidermis using a tattoo device (Fig.…”

Section: Isg15 Causes Innate Immune Alert In the Skinmentioning

confidence: 99%

IFN-Stimulated Gene 15 Is an Alarmin that Boosts the CTL Response via an Innate, NK Cell–Dependent Route

Iglesias-Guimarais

Ahrends

Vries

et al. 2020

The Journal of Immunology

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Type I IFN is produced upon infection and tissue damage and induces the expression of many IFN-stimulated genes (ISGs) that encode host-protective proteins. ISG15 is a ubiquitin-like molecule that can be conjugated to proteins but is also released from cells in a free form. Free, extracellular ISG15 is suggested to have an immune-regulatory role, based on disease phenotypes of ISG15-deficient humans and mice. However, the underlying mechanisms by which free ISG15 would act as a “cytokine” are unclear and much debated. We, in this study, demonstrate in a clinically relevant mouse model of therapeutic vaccination that free ISG15 is an alarmin that induces tissue alert, characterized by extracellular matrix remodeling, myeloid cell infiltration, and inflammation. Moreover, free ISG15 is a potent adjuvant for the CTL response. ISG15 produced at the vaccination site promoted the vaccine-specific CTL response by enhancing expansion, short-lived effector and effector/memory differentiation of CD8+ T cells. The function of free ISG15 as an extracellular ligand was demonstrated, because the equivalents in murine ISG15 of 2 aa recently implicated in binding of human ISG15 to LFA-1 in vitro were required for its adjuvant effect in vivo. Moreover, in further agreement with the in vitro findings on human cells, free ISG15 boosted the CTL response in vivo via NK cells in the absence of CD4+ T cell help. Thus, free ISG15 is part of a newly recognized innate route to promote the CTL response.

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“…CD4 T cells also promote the ultimate positioning of memory CD8 T cells in the infected respiratory tract (30). Intriguingly, a recent study provided strong evidence that CD4 T cell “help” is critical for development of effector CD8 T cells that have cytotoxic potential, and express molecules critical for homing and extravasation, all key to protective immunity to influenza (31). In addition to potentiating the protective function of other cells in the antigen-specific adaptive response, CD4 T cell memory also likely plays a role in recruitment of early innate effector cells into the lung (32, 33), promoting a complex array of effector mechanisms that can blunt virus infection and replication (reviewed in (34)).…”

Section: Overview: the Contributions Of Cd4 T Cells To Protection Fromentioning

confidence: 99%

CD4 T cells in protection from influenza virus: Viral antigen specificity and functional potential

Sant

DiPiazza

Nayak

et al. 2018

Immunological Reviews

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CD4 T cells convey a number of discrete functions to protective immunity to influenza, a complexity that distinguishes this arm of adaptive immunity from B cells and CD8 T cells. Although the most well recognized function of CD4 T cells is provision of help for antibody production, CD4 T cells are important in many aspects of protective immunity. Our studies have revealed that viral antigen specificity is a key determinant of CD4 T cell function, as illustrated both by mouse models of infection and human vaccine responses, a factor whose importance is due at least in part to events in viral antigen handling. We discuss research that has provided insight into the diverse viral epitope specificity of CD4 T cells elicited after infection, how this primary response is modified as CD4 T cells home to the lung, establish memory, and after challenge with a secondary and distinct influenza virus strain. Our studies in human subjects point out the challenges facing vaccine efforts to facilitate responses to novel and avian strains of influenza, as well as strategies that enhance the ability of CD4 T cells to promote protective antibody responses to both seasonal and potentially pandemic strains of influenza.

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CD4+ T Cell Help Confers a Cytotoxic T Cell Effector Program Including Coinhibitory Receptor Downregulation and Increased Tissue Invasiveness

Cited by 316 publications

References 40 publications

Harnessing neoantigen specific CD4 T cells for cancer immunotherapy

Harnessing neoantigen specific CD4 T cells for cancer immunotherapy

IFN-Stimulated Gene 15 Is an Alarmin that Boosts the CTL Response via an Innate, NK Cell–Dependent Route

CD4 T cells in protection from influenza virus: Viral antigen specificity and functional potential

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