Journal
BIOMATERIALS
Volume 159, Issue -, Pages 130-145Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2017.12.019
Keywords
Chlamydia muridarum; Nanovaccine; Caveolin; Dendritic cells; Endocytosis; PLA-PEG nanoparticles
Funding
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) [R21AI111159]
- NIH-NIGMS-RISE [1R25GM106995-01]
- National Science Foundation (NSF) CREST [HRD-1241701]
- NIH [P30 AI027767]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R21AI111159, P30AI027767] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R25GM106995] Funding Source: NIH RePORTER
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We previously developed a Chlamydia trachomatis nanovaccine (PPM) by encapsulating a chlamydial M278 peptide within poly(lactic acid)-poly(ethylene glycol) biodegradable nanoparticles that immunopotentiated Chlamydia-specific immune effector responses in mice. Herein, we investigated the mechanistic interactions of PPM with mouse bone marrow-derived dendritic cells (DCs) for its uptake, trafficking, and T cell activation. Our results reveal that PPM triggered enhanced expression of effector cytokines and chemokines, surface activation markers (Cd1d2, Fcgr1), pathogen-sensing receptors (TLR2, Nod1), co-stimulatory (CD40, CD80, CD86) and MHC class I and II molecules. Co-culturing of PPM-primed DCs with T cells from C muridarum vaccinated mice yielded an increase in Chlamydia-specific immune effector responses including CD3(+) lymphoproliferation, CD3(+)CD4(+) IFN-gamma-secreting cells along with CD3(+)CD4(+) memory (CD44(high) and CD62L(high)) and effector (CD44(high) and CD62L(low)) phenotypes. Intracellular trafficking analyses revealed an intense expression and colocalization of PPM predominantly in endosomes. PPM also upregulated the transcriptional and protein expression of the endocytic mediator, caveolin(-1) in DCs. More importantly, the specific inhibition of caveolin-1 led to decreased expression of PPM-induced cytokines and co-stimulatory molecules. Our investigation shows that PPM provided enhancement of uptake, probably by exploiting the caveolin-mediated endocytosis pathway, endosomal processing, and MHC II presentation to immunopotentiate Chlamydia-specific immune effector responses mediated by CD4(+) T cells. (C) 2017 Elsevier Ltd. All rights reserved.
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