A simple method for measuring immune complex-mediated, Fc gamma receptor dependent antigen-specific activation of primary human T cells

Junker, Fabian; Krishnarajah, Sinduya; Qureshi, Omar; Humphreys, David P.; Fallah-Arani, Farnaz

doi:10.1016/j.jim.2017.12.002

Cited by 7 publications

(9 citation statements)

References 51 publications

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“…Important differences in FcγR-triggered cytokine production between humans and mice have been reviewed by Vogelpoel et al ( 116 ). Finally, our own studies using human primary cell-derived assay systems showed that stronger T cell responses to tetanus toxoid were induced by human monocyte derived DCs, or in total PBMC cultures, when challenged with the IgG-coated antigen as opposed to the “naked” antigen alone ( 117 , 118 ). Tetanus toxoid IgG-ICs significantly enhanced the production of pro-inflammatory cytokines IFN-γ, TNF-α, and IL-1β, whilst FcγR-blockade with a multivalent Fc-containing molecule, or with a cocktail of FcγR blocking antibodies, abrogated this response confirming the importance of FcγRs in mediating this enhancement.…”

Section: Fcγr Mediated Effects On Apcs: Antigen Uptake and T Cell Primentioning

confidence: 99%

Fc Gamma Receptors and Their Role in Antigen Uptake, Presentation, and T Cell Activation

2020

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The cellular uptake, intracellular processing, and presentation of foreign antigen are crucial processes for eliciting an effective adaptive host response to the majority of pathogens. The effective recognition of antigen by T cells requires that it is first processed and then presented on MHC molecules that are expressed on other cells. A critical step leading to the presentation of antigen is delivering the foreign cargo to an intracellular compartment where the antigen can be processed and loaded onto MHC molecules. Fc-gamma receptors (FcγRs) recognize IgG-coated targets, such as opsonized pathogens or immune complexes (ICs). Cross-linking leads to internalization of the cargo with associated activation of downstream signaling cascades. FcγRs vary in their affinity for IgG and intracellular trafficking, and therefore have an opportunity to regulate antigen presentation by controlling the shuttling and processing of their cargos. In this way, they critically influence physiological and pathophysiological adaptive immune cell functions. In this review, we will cover the contribution of FcγRs to antigenpresentation with a focus on the intracellular trafficking of IgG-ICs and the pathways that support this function. We will also discuss genetic evidence linking FcγR biology to immune cell activation and autoimmune processes as exemplified by systemic lupus erythematosus (SLE).

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Section: Fcγr Mediated Effects On Apcs: Antigen Uptake and T Cell Primentioning

confidence: 99%

Fc Gamma Receptors and Their Role in Antigen Uptake, Presentation, and T Cell Activation

2020

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“…In addition to PRRs, DCs express Fc-gamma receptors (FcγR) that can lead to a highly effective internalization of Ag and subsequent DC activation [55]. FcγRs, when crosslinked through IgG antibody-complexed ("opsonized") soluble Ag, allow for rapid internalization and cellular activation [56,57]. This immune complex (IC) will then be shuttled to endolysosomal DC compartments, where the Ag will subsequently be degraded.…”

Section: Fcγr Crosslinking On Dcs Leads To Effective T-cell Activation and Proliferationmentioning

confidence: 99%

“…Several lines of evidence, both in humans and mice, have convincingly demonstrated that IgG:Ag ICs induce a superior DC activation compared to the delivery of uncoated, "naked" Ag [56,57]. For example, pulsing in vitro human moDCs with polyclonal tetanus IgG ICs led to a stronger increase in DC activation, including the release of proinflammatory cytokines compared to "naked" tetanus toxoid Ag [57,70]. Similarly, in a pivotal mouse study, ovalbumin (OVA) preincubated with anti-OVA IgG was taken up much more efficiently by splenic mouse DCs ex vivo than "naked" OVA.…”

Section: Fcγr Crosslinking On Dcs Leads To Effective T-cell Activation and Proliferationmentioning

confidence: 99%

“…Here, in a polyclonal tetanus:IgG IC model, tetanus-induced T-cell proliferation was not significantly reduced at high doses of hexameric Fc. In this model, DCs are assumed to be the major T cell-activating cell type [57]. Given the purported MoA of Fc multimers resulting in the degradation of activating FcγRs, this would advocate for a critical role of FcγRIIB in IC-mediated T-cell activation, at least in the case of poorly defined polyclonal tetanus:IgG ICs.…”

Section: Recombinant Igg Ics To Target Human Fcγrsmentioning

confidence: 99%

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Dendritic Cell Tumor Vaccination via Fc Gamma Receptor Targeting: Lessons Learned from Pre-Clinical and Translational Studies

2021

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Despite significant recent improvements in the field of immunotherapy, cancer remains a heavy burden on patients and healthcare systems. In recent years, immunotherapies have led to remarkable strides in treating certain cancers. However, despite the success of checkpoint inhibitors and the advent of cellular therapies, novel strategies need to be explored to (1) improve treatment in patients where these approaches fail and (2) make such treatments widely and financially accessible. Vaccines based on tumor antigens (Ag) have emerged as an innovative strategy with the potential to address these areas. Here, we review the fundamental aspects relevant for the development of cancer vaccines and the critical role of dendritic cells (DCs) in this process. We first offer a general overview of DC biology and routes of Ag presentation eliciting effective T cell-mediated immune responses. We then present new therapeutic avenues specifically targeting Fc gamma receptors (FcγR) as a means to deliver antigen selectively to DCs and its effects on T-cell activation. We present an overview of the mechanistic aspects of FcγR-mediated DC targeting, as well as potential tumor vaccination strategies based on preclinical and translational studies. In particular, we highlight recent developments in the field of recombinant immune complex-like large molecules and their potential for DC-mediated tumor vaccination in the clinic. These findings go beyond cancer research and may be of relevance for other disease areas that could benefit from FcγR-targeted antigen delivery, such as autoimmunity and infectious diseases.

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“…Furthermore, the recent development of a simple cellular assay of IC-mediated T-cell activation in vitro using human peripheral blood mononuclear cells, may help to evaluate the efficacy of ICs prior to clinical trials. 95 Notably, due to the small dosage of monoclonal antibodies used to generate ICs, it will also be intrinsically less expensive to produce ICs than therapeutic antibodies. Furthermore, the tedious and expensive process of separately producing qualified antigen and antibody may be avoidable.…”

Section: Perspectivesmentioning

confidence: 99%

From therapeutic antibodies to immune complex vaccines

Wang

Wen

2019

npj Vaccines

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In recent years, therapeutic monoclonal antibodies have made impressive progress, providing great benefit by successfully treating malignant and chronic inflammatory diseases. Monoclonal antibodies with broadly neutralizing effects against specific antigens, or that target specific immune regulators, manifest therapeutic effects via their Fab fragment specificities. Subsequently therapeutic efficacy is mediated mostly by interactions of the Fc fragments of the antibodies with their receptors (FcR) displayed on cells of the immune system. These interactions can trigger a series of immunoregulatory responses, involving both innate and adaptive immune systems and including cross-presentation of antigens, activation of CD8+ T cells and CD4+ T cells, phagocytosis, complement-mediated antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). The nature of the triggered effector functions of the antibodies is markedly affected by the glycosylation patterns of the Fc fragments. These can cause differences in the conformation of the heavy chains of antibodies, with resultant changes in antibody binding affinity and activation of the complement system. Studies of the Fc glycosylation profiles together with the associated Fc effector functions and FcR/CR interactions promoted interest and progress in engineering therapeutic antibodies. Furthermore, because antigen–antibody immune complexes (ICs) have shown similar actions, in addition to certain novel immunoregulatory mechanisms that also reshape immune responses, the properties of ICs are being explored in new approaches for prevention and therapy of diseases. In this review, both basic studies and experimental/clinical applications of ICs leading to the development of preventive and therapeutic vaccines are presented.

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A simple method for measuring immune complex-mediated, Fc gamma receptor dependent antigen-specific activation of primary human T cells

Cited by 7 publications

References 51 publications

Fc Gamma Receptors and Their Role in Antigen Uptake, Presentation, and T Cell Activation

Fc Gamma Receptors and Their Role in Antigen Uptake, Presentation, and T Cell Activation

Dendritic Cell Tumor Vaccination via Fc Gamma Receptor Targeting: Lessons Learned from Pre-Clinical and Translational Studies

From therapeutic antibodies to immune complex vaccines

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