IL-10 production differentially influences the magnitude, quality, and protective capacity of Th1 responses depending on the vaccine platform.
The quality of a Th1 response can be a prospective correlate of vaccine-mediated protection against certain intracellular pathogens. Using two distinct vaccine platforms, we evaluate the influence of interleukin (IL) 10 production on the magnitude, quality, and protective capacity of CD4(+) T cell responses in the mouse model of Leishmania major infection. Multiparameter flow cytometry was used to delineate the CD4(+) T cell production of interferon (IFN) gamma, IL-2, tumor necrosis factor (TNF), and IL-10 (or combinations thereof) after vaccination. Immunization with a high dose of adenovirus (ADV) expressing leishmanial proteins (MML-ADV) elicited a limited proportion of multifunctional IFN-gamma(+)IL-2(+)TNF(+) Th1 cells, a high frequency of IL-10-producing CD4(+) T cells, and did not protect against subsequent challenge. Surprisingly, in the absence of IL-10, there was no change in the magnitude, quality, or protective capacity of the Th1 response elicited by high-dose MML-ADV. In contrast, after immunization with MML protein and CpG (MML + CpG), IL-10 limited the production of IL-12 by DCs in vivo, thereby decreasing the generation of multifunctional Th1 cells. Consequently, three immunizations with MML + CpG were required for full protection. However, inhibiting IL-10 at the time of immunization enhanced the magnitude and quality of the Th1 response sufficiently to mediate protection after only a single immunization. Overall, we delineate distinct mechanisms by which vaccines elicit protective Th1 responses and underscore the importance of multifunctional CD4(+) T cells.
Cellular Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Patricia A
PA
Darrah
Sonia T
ST
Hegde
Dipti T
DT
Patel
Ross W B
RW
Lindsay
Linda
L
Chen
Mario
M
Roederer
Robert A
RA
Seder
D000256:Adenoviridae / Q000276:immunology; D000818:Animals; D005260:Female; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology*; D007114:Immunization; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000276:immunology; D015800:Protozoan Proteins / Q000276:immunology; D016052:Protozoan Vaccines / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*
C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D015800:Protozoan Proteins; D016052:Protozoan Vaccines; D016753:Interleukin-10; D018664:Interleukin-12