Differential requirements for CTL generation by novel immunostimulants: APC tropism, use of the TAP-independent processing pathway, and dependency on CD80/CD86 costimulation.
A major drawback of subunit vaccines is their inability to generate cytolytic T lymphocytes (CTL), a deficit attributed to segregation of the class I and class II antigen-processing pathways. We sought to understand processes involved in CTL induction by three proprietary adjuvants: Tomatine, PROVAX, and a synthesized glycolipid (Glc-N-(8/16), Glycolipid). We used in vivo models to investigate antigen uptake, macrophage involvement, TAP-independent processing, and costimulatory molecule dependencies. Glycolipid required splenic and lymph node macrophages, whereas Tomatine generated CTL independently of either macrophage population. In contrast, PROVAX showed partial macrophage requirements. Immunized TAP knockout mice revealed that ovalbumin (OVA)-Tomatine and OVA-PROVAX, but not OVA-Glycolipid, generate class I-peptide complexes. All three immunostimulants also elicited CD86-dependent TH1 cytokine responses.
Sheikh
Nadeem A
NA
Department of Immunology, St. Bartholomew's and the Royal London School of Medicine and Dentistry, London, UK. nadeem@u.washington.edu
Attard
George S
GS
van Rooijen
Nico
N
Rajananthanan
Palasingam
P
Hariharan
Kandasamy
K
Yang
Ya-Wun
YW
Morrow
W John W
WJ
D025601:Adenomatous Polyposis Coli Protein / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000941:Antigens / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology*; D051940:B7-2 Antigen; D002216:Captopril / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical; D016207:Cytokines / Q000096:biosynthesis; D004721:Endoplasmic Reticulum / Q000201:enzymology; D005260:Female; D005434:Flow Cytometry; D008264:Macrophages / Q000276:immunology / Q000502:physiology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D010455:Peptides / Q000276:immunology; D007703:Peptidyl-Dipeptidase A / Q000502:physiology; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000502:physiology*
D025601:Adenomatous Polyposis Coli Protein; D000276:Adjuvants, Immunologic; D000806:Angiotensin-Converting Enzyme Inhibitors; D000941:Antigens; D015703:Antigens, CD; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D016207:Cytokines; D008562:Membrane Glycoproteins; D010455:Peptides; D010047:Ovalbumin; D002216:Captopril; D007703:Peptidyl-Dipeptidase A