Induction of Mycobacterium Tuberculosis Lipid-Specific T Cell Responses by Pulmonary Delivery of Mycolic Acid-Loaded Polymeric Micellar Nanocarriers

Shang, Shaobin; Kats, Dina; Cao, Liang; Morgun, Eva; Velluto, Diana; Xu, Qichen; Wang, Chyung Ru; Scott, Evan A.

doi:10.3389/fimmu.2018.02709

Cited by 41 publications

(45 citation statements)

References 51 publications

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“…Afterward, Huang and co‐workers used micelles made from PEG conjugated to curcumin (a polyphenol) to deliver the lipid‐based Trp2 peptide, which increased CTL induction as well as TNF‐α and IFN‐γ secretion . In addition to cancer vaccines, synthetic micelles have also been used to vaccinate against chlamydia and mycobacterium tuberculosis . In the former case, PLA was conjugated to resiquimod, which self‐assembles with the PLGA domain of a PLGA‐PEG conjugate to form a micelle‐like nanoparticle.…”

Section: Nanoscale Materials For Immunotherapymentioning

confidence: 99%

Materials for Immunotherapy

et al. 2019

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Breakthroughs in materials engineering have accelerated the progress of immunotherapy in preclinical studies. The interplay of chemistry and materials has resulted in improved loading, targeting, and release of immunomodulatory agents. An overview of the materials that are used to enable or improve the success of immunotherapies in preclinical studies is presented, from immunosuppressive to proinflammatory strategies, with particular emphasis on technologies poised for clinical translation. The materials are organized based on their characteristic length scale, whereby the enabling feature of each technology is organized by the structure of that material. For example, the mechanisms by which i) nanoscale materials can improve targeting and infiltration of immunomodulatory payloads into tissues and cells, ii) microscale materials can facilitate cell‐mediated transport and serve as artificial antigen‐presenting cells, and iii) macroscale materials can form the basis of artificial microenvironments to promote cell infiltration and reprogramming are discussed. As a step toward establishing a set of design rules for future immunotherapies, materials that intrinsically activate or suppress the immune system are reviewed. Finally, a brief outlook on the trajectory of these systems and how they may be improved to address unsolved challenges in cancer, infectious diseases, and autoimmunity is presented.

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Section: Nanoscale Materials For Immunotherapymentioning

confidence: 99%

Materials for Immunotherapy

et al. 2019

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“…These findings suggest that CD4, and not CD8, T cells may be the major CD1b-restricted T cell subset activated during active TB, possibly as a result of enhanced functional avidity. Lipid-based vaccines have shown promise in pre-clinical animal models (Shang et al, 2018). Our data highlight the importance of considering whether CD4 or CD8 T cells would be targeted by the adjuvant or delivery platform when ‘tuning’ the chemical structure of the antigen to modify TCR avidity and immunogenicity of these novel vaccine strategies.…”

Section: Discussionmentioning

confidence: 99%

CD4 and CD8 co-receptors modulate functional avidity of CD1b-restricted T cells

James

Aguilar

et al. 2020

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CD4 and CD8 co-receptors define distinct lineages of T cells restricted by major histocompatibility complex (MHC) Class II and I molecules, respectively. Co-receptors interact with the T cell receptor (TCR) at the surface of MHC-restricted T cells to facilitate antigen recognition, thymic selection, and functional differentiation. T cells also recognize lipid antigens presented by CD1 molecules, but the role that CD4 and CD8 play in lipid antigen recognition is unknown. We studied the effect of CD4 and CD8 on the avidity, activation, and function of T cells specific for two CD1b-presented mycobacterial lipid antigens, glucose monomycolate (GMM) and diacylated sulfoglycolipids (SGL). In a human cohort study using SGL-loaded CD1b tetramers, we discovered a hierarchy among SGL-specific T cells in which T cells expressing the CD4 or CD8 co-receptor stain with a higher tetramer mean fluorescence intensity (MFI) than CD4-CD8- T cells. To determine the role of the TCR co-receptor in lipid antigen recognition, we exogenously expressed GMM and SGL-specific TCRs in Jurkat or polyclonal T cells and quantified tetramer staining and activation thresholds. Transduced CD4+ primary T cells bound the lipid-loaded CD1b tetramer with a higher MFI than CD8+ primary T cells, and transduced CD8+ Jurkat cells bound the SGL-CD1b tetramer with higher MFI than CD4-CD8- Jurkat cells. The presence of either co-receptor also decreased the threshold for IFN-γ secretion. Further, co-receptor expression increased surface expression of CD3ε, suggesting a mechanism for increased tetramer binding and activation. Finally, we used single-cell sequencing to define the TCR repertoire and ex vivo functional profiles of SGL-specific T cells from individuals with M.tb disease. We found that CD8+ T cells specific for SGL express canonical markers associated with cytotoxic T lymphocytes, while CD4+ T cells could be classified as T regulatory or T follicular helper cells. Among SGL-specific T cells, only those expressing the CD4 co-receptor also expressed Ki67, suggesting that they were actively proliferating at the time of sample collection. Together, these data reveal that expression of CD4 and CD8 co-receptor modulates TCR avidity for lipid antigen, leading to functional diversity and differences in in vivo proliferation during M.tb disease.

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“…In this study, self-assembled micellar nanocarriers composed of poly(ethylene glycol)-b-poly(propylene sulfide) (PEG-b-PPS) are validated as a platform to deliver an effective surface density of the anti-angiogenic peptide GHSDVHK. PEG-b-PPS self-assembles into a diverse range of nanocarrier morphologies that possess dense PEG coronas to inhibit nonspecific protein adsorption as well as hydrophobic PPS domains for retention of lipophilic payloads [41][42][43][44]. Recently, Stack et al employed PEG-b-PPS micelles for targeted intracellular delivery of latrunculin A as a treatment for glaucoma [45].…”

Section: Introductionmentioning

confidence: 99%

High Density Display of an Anti-Angiogenic Peptide on Micelle Surfaces Enhances Their Inhibition of αvβ3 Integrin-Mediated Neovascularization In Vitro

Nagaraj

Stack

et al. 2020

Nanomaterials

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Diabetic retinopathy (DR), Retinopathy of Pre-maturity (ROP), and Age-related Macular Degeneration (AMD) are multifactorial manifestations associated with abnormal growth of blood vessels in the retina. These three diseases account for 5% of the total blindness and vision impairment in the US alone. The current treatment options involve heavily invasive techniques such as frequent intravitreal administration of anti-VEGF (vascular endothelial growth factor) antibodies, which pose serious risks of endophthalmitis, retinal detachment and a multitude of adverse effects stemming from the diverse physiological processes that involve VEGF. To overcome these limitations, this current study utilizes a micellar delivery vehicle (MC) decorated with an anti-angiogenic peptide (aANGP) that inhibits αvβ3 mediated neovascularization using primary endothelial cells (HUVEC). Stable incorporation of the peptide into the micelles (aANGP-MCs) for high valency surface display was achieved with a lipidated peptide construct. After 24 h of treatment, aANGP-MCs showed significantly higher inhibition of proliferation and migration compared to free from aANGP peptide. A tube formation assay clearly demonstrated a dose-dependent angiogenic inhibitory effect of aANGP-MCs with a maximum inhibition at 4 μg/mL, a 1000-fold lower concentration than that required for free from aANGP to display a biological effect. These results demonstrate valency-dependent enhancement in the therapeutic efficacy of a bioactive peptide following conjugation to nanoparticle surfaces and present a possible treatment alternative to anti-VEGF antibody therapy with decreased side effects and more versatile options for controlled delivery.

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Induction of Mycobacterium Tuberculosis Lipid-Specific T Cell Responses by Pulmonary Delivery of Mycolic Acid-Loaded Polymeric Micellar Nanocarriers

Cited by 41 publications

References 51 publications

Materials for Immunotherapy

Materials for Immunotherapy

CD4 and CD8 co-receptors modulate functional avidity of CD1b-restricted T cells

High Density Display of an Anti-Angiogenic Peptide on Micelle Surfaces Enhances Their Inhibition of αvβ3 Integrin-Mediated Neovascularization In Vitro

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