Supramolecular Peptide Nanofibers Engage Mechanisms of Autophagy in Antigen-Presenting Cells

Rudra, Jai S.; Khan, Arshad; Clover, Tara M.; Endsley, Janice J.; Zloza, Andrew; Wang, Jin; Jagannath, Chinnaswamy

doi:10.1021/acsomega.7b00525

Cited by 20 publications

(23 citation statements)

References 33 publications

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“…Furthermore, it was demonstrated that the incorporation of Tat peptide into epitope‐bearing nanofiber (OVA.Tat 12.5 nanofibers) considerably improved specific CD8+ T cell responses. In consistent with our result, other studies have also demonstrated that incorporation of CD8+ T cell epitopes into nanofibers could induce stronger specific CD8+ T cell responses without the need of adding an adjuvant, compared with soluble epitopes or soluble epitopes mixed with nanofibers (Rudra, Khan et al, 2017; Si et al, 2018). Furthermore, J. Chen et al (2013) showed that epitopes incorporated into nanofibers‐induced immune responses that were stronger than emulsions with alum, and responses that were comparable with Freund's adjuvant, but without adjuvants‐related side effects.…”

Section: Discussionsupporting

confidence: 93%

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Incorporation of the Tat cell‐penetrating peptide into nanofibers improves the respective antitumor immune response

Mohammadi

Dehghani

Mohseninia

et al. 2020

Journal Cellular Physiology

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A major challenge for the development of anticancer vaccines is the induction of a safe and effective immune response, particularly mediated by CD8+ T lymphocytes, in an adjuvant-free manner. In this respect, we present a simple strategy to improve the specific CD8+ T cell responses using KFE8 nanofibers bearing a Class I (Kb)-restricted peptide epitope (called E. nanofibers) without the use of adjuvant. We demonstrate that incorporation of Tat, a cell-penetrating peptide (CPP) of the HIV transactivator protein, into E. nanofibers remarkably enhanced tumor-specific CD8+ T cell responses. E. nanofibers containing 12.5% Tat peptide (E.Tat 12.5 nanofiber) increased antigen cross-presentation by bone marrow-derived dendritic cells as compared with E. nanofibers, or E. nanofibers containing 25 or 50% the Tat peptide. Uptake of KFE8.Tat 12.5 nanofibers by dendritic cells (DCs) was significantly increased compared with KFE8 nanofiber lacking Tat. Peritoneal and lymph node DCs of mice immunized with E.Tat 12.5 nanofibers exhibited increased presentation of the H2kb-epitope (reminiscent for cross-presentation) compared with DCs obtained from E. nanofiber vaccinated mice. Tetrameric and intracellular cytokine staining revealed that vaccination with E.Tat 12.5 triggered a robust and specific CD8+ T lymphocyte response, which was more pronounced than in mice vaccinated with E. nanofibers alone. Furthermore, E.Tat 12.5 nanofibers were more potent than E. nanofiber to induce antitumor immune response and tumorinfiltrating IFN-γ CD8 T lymphocyte. In terms of cancer vaccine development, we propose that harnessing the nanofiber-based vaccine platform with incorporated Tat peptide could present a simple and promising strategy to induce highly effective antitumor immune response.

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Section: Discussionsupporting

confidence: 93%

“…According to results from previous studies (Chesson et al, 2018;Rudra, Sun et al, 2012;Rudra, Tian, Jung, & Collier, 2010;Si et al, 2018), peptide-based nanofibers when used as a (Rudra, Khan et al, 2017;Si et al, 2018). Furthermore, J.…”

Section: Discussionmentioning

confidence: 92%

Incorporation of the Tat cell‐penetrating peptide into nanofibers improves the respective antitumor immune response

Mohammadi

Dehghani

Mohseninia

et al. 2020

Journal Cellular Physiology

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“…In studies to date, peptide nanofiber vaccines have been used without added adjuvants and we recently reported that the immunogenicity of peptide nanofiber vaccines is due to enhanced macroautophagy-mediated antigen presentation 35 . However, the nanofibers themselves do not activate APCs similar to adjuvants that activate pathogen pattern recognition receptors such as TLR agonists that provide additional signals that direct T cell memory development 36 , 37 .…”

Section: Resultsmentioning

confidence: 99%

Nanoscale Peptide Self-assemblies Boost BCG-primed Cellular Immunity Against Mycobacterium tuberculosis

Chesson

Huante

Nusbaum

et al. 2018

Sci Rep

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Bacillus Calmette-Guerin (BCG) is the only vaccine against TB and has limited protection efficacy, which wanes past adolescence. Multifunctional CD8+ T cells (IFN-γ+/TNF-α+/IL-2+) are associated with lower reactivation risk and enhanced control of active Mtb infection. Since boosting with BCG is contraindicated, booster vaccines that augment T cell immunity in the lungs of BCG-vaccinated individuals are urgently needed. We developed a vaccination strategy based on self-assembling peptide nanofibers presenting Mtb-specific CD8+ or CD4+ T cell epitopes that induce high frequency and antigen-specific effector memory T cells producing IFN-γ and IL-2. Intranasal immunization with peptide nanofibers was well tolerated in mice leading to increased antigen-specific CD8+ T cell population in the lungs. Co-assembled nanofibers of CD8+ T cell epitopes and toll-like receptor 2 (TLR2) agonists induced a 8-fold expansion in multifunctional CD8+ T cell populations in the lungs of vaccinated mice. Aerosol challenge with Mtb in BCG-primed and nanofiber-boosted mice provided an additional 0.5-log CFU reduction in lung bacterial load and indicating enhanced protection compared to BCG alone. Together, these data suggest that heterologous prime-boost with BCG and peptide nanofiber vaccines induces cell mediated immunity in the lung, reduces bacterial burden, and is a potentially safer alternative for boosting BCG-primed immunity.

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“…Increasing autophagy-mediated Ag presentation has been demonstrated as a simple and powerful strategy to improve vaccine efficiency, as in the case of the BCG vaccine 22 . Autophagy-inducing small molecules or peptides have been demonstrated as potential adjuvants through their enhancement of Ag delivery, processing and presentation [47][48][49] . Combination with TLR2-stimulating peptide or LPS in BCG vaccines can induce autophagy in APCs and promote immunogenicity days.…”

Section: Discussionmentioning

confidence: 99%

Vaccine adjuvant activity of a TLR4-activating synthetic glycolipid by promoting autophagy

Chou

Lin²,

Dzhagalov³

et al. 2020

Sci Rep

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Toll-like receptors (TLRs) play crucial roles in host immune defenses. Recently, TLR-mediated autophagy is reported to promote immune responses via increasing antigen processing and presentation in antigen presenting cells. The present study examined whether the synthetic TLR4 activator (CCL-34) could induce autophagy to promote innate and adaptive immunity. In addition, the potential of CCL-34 as an immune adjuvant in vivo was also investigated. Our data using RAW264.7 cells and bone marrow-derived macrophages showed that CCL-34 induced autophagy through a TLR4-NF-κB pathway. The autophagy-related molecules (Nrf2, p62 and Beclin 1) were activated in RAW264.7 cells and bone marrow-derived macrophages under CCL-34 treatment. CCL-34-stimulated macrophages exhibited significant antigen-processing activity and induced the proliferation of antigen-specific CD4+T cells as well as the production of activated T cell-related cytokines, IL-2 and IFN-γ. Furthermore, CCL-34 immunization in mice induced infiltration of monocytes in the peritoneal cavity and elevation of antigen-specific IgG in the serum. CCL-34 treatment in vivo did not cause toxicity based on serum biochemical profiles. Notably, the antigen-specific responses induced by CCL-34 were attenuated by the autophagy inhibitor, 3-methyladenine. In summary, we demonstrated CCL-34 can induce autophagy to promote antigen-specific immune responses and act as an efficient adjuvant. Vaccine development holds a great contribution in infectious disease prevention and cancer immunotherapy. Vaccines contain both antigens and adjuvants to induce antigen (Ag)-specific antibody responses. Adjuvants are required to boost Ag-specific adaptive immune response in B cells and T cells. The current strategies of vaccine development to trigger early immune responses are via enhancing Ag uptake in antigen-presenting cells (APCs), providing appropriate microenvironments for APC activations, and further promoting the differentiation of naïve T cells into effector T cells 1,2. Currently licensed adjuvants in clinical applications, such as AS04, MF59 and Alum, were reported to activate pattern recognition receptors (PRRs) and/or NLRP3 inflammasome, which trigger humoral antibody responses accompanied with T cell responses 1,3-5. Recent studies showed that stimulation of autophagy is able to augment T cell responses via modulating the functions in both APCs and T cells 6. The autophagy/lysosome degradation pathway is an evolutionarily conserved stress response mechanism for survival 7 , and its dysregulation plays critical roles in human diseases 8. During infection, one of the major immune mechanisms against pathogens is to induce canonical and noncanonical autophagy in macrophages. The canonical selective autophagy (xenophagy) selectively captures and degrades intracellular mycobacteria, such as Mycobacterium tuberculosis and Listeria monocytogenes 9,10. Moreover, the noncanonical autophagy, LC3-associated phagocytosis (LAP), can accelerate pathogen clearance 11-15. Furthermore, induction o...

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Supramolecular Peptide Nanofibers Engage Mechanisms of Autophagy in Antigen-Presenting Cells

Cited by 20 publications

References 33 publications

Incorporation of the Tat cell‐penetrating peptide into nanofibers improves the respective antitumor immune response

Incorporation of the Tat cell‐penetrating peptide into nanofibers improves the respective antitumor immune response

Nanoscale Peptide Self-assemblies Boost BCG-primed Cellular Immunity Against Mycobacterium tuberculosis

Vaccine adjuvant activity of a TLR4-activating synthetic glycolipid by promoting autophagy

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