Comparison of OX40 Ligand and CD70 in the Promotion of CD4+ T Cell Responses

Kurche, Jonathan S.; Burchill, Matthew A.; Sanchez, Phillip J.; Haluszczak, Catherine; Kedl, Ross M.

doi:10.4049/jimmunol.1000172

Cited by 30 publications

(57 citation statements)

References 59 publications

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“…Much like the B cell response, the use of either of these single adjuvants typically produces around 10–50,000 total antigen specific CD8+ T cells [2], a number that is non-protective with respect to T cell responses [13]. In contrast, after a single exposure, the combined innate/CD40 adjuvant can produce a similar number of antigen specific T cells (~1–3 million antigen specific T cells), and in the same time frame (7 days), as the infectious challenge [2, 10, 13, 44, 45]. As a result of the potency of this vaccine adjuvant, we and others [46–48] have spent years studying its underlying mechanisms in mice and have recently shown its capacity to produce robust CD8 and CD4 responses in non-human primates [49].…”

Section: T Cell Vs B Cell Fauna… All About the Numbersmentioning

confidence: 99%

“…In hindsight, we should not have been surprised to find that rather than revealing secrets of the hidden infectious process, we identified signals central only to the efficacy of subunit vaccine adjuvants. Thus far, two signaling pathways have stood out as critical to vaccine-elicited CD8+ T cell responses; CD27 [10, 12, 13, 45] and (coincidently) IL-27 [2]. While the “27s” also influence and modulate the infectious response, their role in the infection is far more qualitative and nuanced than in vaccination where they dictate (in a necessary-but-not-sufficient manner) the magnitude of the primary response and the function of the memory response.…”

Section: T Cell Vs B Cell Fauna… All About the Numbersmentioning

confidence: 99%

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T Cell Vaccinology: Beyond the Reflection of Infectious Responses

Pennock

Kedl

2016

Trends in Immunology

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Inducing sustained, robust CD8+ T cell responses is necessary for therapeutic intervention in chronic infectious diseases and cancer. Unfortunately, most adjuvant formulations fail to induce substantial cellular immunity in humans. Attenuated acute infectious agents induce strong CD8+ T cell immunity, and are thought to therefore represent a good road map for guiding the development of subunit vaccines capable of inducing the same. However, recent evidence suggests that this assumption may need reconsideration. Here we provide an overview of subunit vaccine history as it pertains to instigating T cell responses. We argue that in light of evidence demonstrating that T cell responses to vaccination differ from those induced by infectious challenge, research in pursuit of cellular immunity-inducing vaccine adjuvants should no longer follow only the infection paradigm.

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Section: T Cell Vs B Cell Fauna… All About the Numbersmentioning

confidence: 99%

Section: T Cell Vs B Cell Fauna… All About the Numbersmentioning

confidence: 99%

T Cell Vaccinology: Beyond the Reflection of Infectious Responses

Pennock

Kedl

2016

Trends in Immunology

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“…For example, we and others have observed that DCs in vitro induce the expression of the TNF ligand CD70 much more readily than DCs in vivo. 32,41,42 Given the potency with which CD70 augments T-cell responses, 32,[41][42][43] particularly with respect to T-cell survival, 44 the success or failure of any specific DC subset to survive and express this one TNF ligand in vitro may impact the conclusion that can be made from the assay. Indeed, the fact that the dermal DC subset was one of the more potent subsets at cross-priming in the standard assay, but was ineffective in our cross-presentation assay may well be related to one or more of the concerns listed above.…”

Section: Tlr7-elicited Cd8 T-cell Response 3035mentioning

confidence: 99%

TLR7 enables cross-presentation by multiple dendritic cell subsets through a type I IFN-dependent pathway

Kurche

Burchill

et al. 2011

Blood

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Conjugation of TLR agonists to protein or peptide antigens has been demonstrated in many studies to be an effective vaccine formula in inducing cellular immunity. However, the molecular and cellular mediators involved in TLR-induced immune responses have not been carefully examined. In this study, we identify Type I IFN and IL-12 as critical mediators of crosspriming induced by a TLR7 agonistantigen conjugate. We demonstrate that TLR7-driven cross-priming requires both Type I IFN and IL-12. Signaling through the IFN-␣␤R was required for the timely recruitment and accumulation of activated dendritic cells in the draining lymph nodes. Although IL-12 was indispensable during cross-priming, it did not regulate DC function. Therefore, the codependency for these 2 cytokines during TLR7-induced cross-priming is the result of their divergent effects on different celltypes. Furthermore, although dermal and CD8␣ ؉ DCs were able to cross-prime CD8 ؉ T cells, Langerhans cells were unexpectedly found to potently cross-present antigen and support CD8 ؉ T-cell expansion, both in vitro and in vivo. Collectively, the data show that a TLR7 agonistantigen conjugate elicits CD8 ؉ T-cell responses by the coordinated recruitment and activation of both tissue-derived and lymphoid organ-resident DC subsets through a Type I IFN and IL-12 codependent mechanism. (Blood. 2011;118(11): 3028-3038) IntroductionActivation of the innate immune system is a prerequisite to initiating adaptive immune responses. A major pathway eliciting these responses is the recognition of foreign bodies through Toll-like receptors (TLR), which results in the activation of antigen presenting cells (APC) and the production of a variety of proinflammatory mediators. 1 Previously, we showed that conjugation of a synthetic agonist targeting TLR7 to protein antigens results in a highly immunogenic vaccine that potently generates protective CD8 ϩ T-cell responses. 2 TLR7 is an intracellular receptor that recognizes single-stranded RNA molecules and detects RNA viruses such as the influenza virus. Stimulation of TLR7 has been shown in both mice and humans to result in vigorous production of multiple pro-inflammatory cytokines, including Type I IFN and IL-12. 3 The induction of Type I IFN and IL-12 is of particular interest given abundant evidence in the literature establishing these 2 cytokines as critical mediators of CD8 ϩ T-cell activation. 4,5 Type I IFN comprises a group of various IFN proteins, notably IFN␣ and IFN␤. IFNs are induced primarily during viral infections and have been shown to promote natural killer (NK), Type I helper T-cell (Th1), and CTL responses, 4 which are critical to combat viral infections through the elimination of virus-infected cells. Similarly, IL-12 also promotes the development of Th1 and CTL-mediated immunity. [6][7][8] However, the production of IL-12 is primarily associated with bacterial and parasitic infections. 7,9 The role of IL-12 during viral infections remains unclear as some reports indicate that CD8 ϩ T-cell responses elicit...

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“…Specifically, the injection of TLR3 agonists combined with CD40 stimulation facilitates the secretion of pro-inflammatory cytokines by CD4 + T cells by promoting the expression of CD134. 40,50 Cross-linking between CD134 on CD4 + T cells and CD252 on activated B cells results in B-cell proliferation and the secretion of all Ig isotypes. 51 This high level of expression of CD134 at 7 days and its involvement in B-cell antibody secretion suggest a direct link between the CD4 + T-cell response and the level of antibody production, which were concordant for the same time interval between agonist injection and transfusion.…”

Section: -40mentioning

confidence: 99%