Analysis of adjuvant function by direct visualization of antigen presentation in vivo: endotoxin promotes accumulation of antigen-bearing dendritic cells in the T cell areas of lymphoid tissue.
T cell activation requires exposure to processed Ag and signaling by cytokines and costimulatory ligands. Adjuvants are thought to enhance immunity primarily through up-regulation of the latter signals. Here, we explore the effect of the bacterial adjuvant, endotoxin, on Ag presentation by B cells and dendritic cells (DC). Using an mAb (C4H3) specific for the hen egg lysozyme (HEL) 46-61 determinant bound to I-Ak, we analyze processed Ag expression and the tissue distribution of presenting cells following systemic administration of soluble HEL to mice. In both LPS-responsive and -hyporesponsive mice given endotoxin-containing HEL, B cells rapidly display surface 46-61/I-Ak complexes. In marked contrast, in LPS-hyporesponsive mice, splenic DC show little gain in C4H3 staining. In LPS-responsive animals, interdigitating DC in T cell areas show no staining above background at early times after HEL administration, but C4H3+ DC rapidly accumulate in the outer periarteriolar lymphoid sheaths (PALS) and in follicular areas. Within a few hours, C4H3+ DC appear in the T cell areas, concomitant with a decline in C4H3+ cells in the outer PALS, suggesting migration between these two sites. Endotoxin enhancement of C4H3 staining is seen for both CD8alpha- and CD8alpha+ DC subsets. These data suggest that a major effect of adjuvants is to promote mobilization of Ag-bearing DC to the T areas of lymphoid tissue, and possibly also to enhance Ag processing by these DC. Thus, microbial products promote T cell immunity not only through DC activation for cosignaling, but through improvement in signal 1 delivery.
Reis e Sousa
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Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
Germain
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D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000941:Antigens / Q000008:administration & dosage* / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016827:CD8 Antigens / Q000096:biosynthesis; D002645:Chickens; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004731:Endotoxins / Q000502:physiology*; D005260:Female; D007275:Injections, Intravenous; D007700:Kinetics; D008221:Lymphoid Tissue / Q000166:cytology* / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009113:Muramidase / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology
D000276:Adjuvants, Immunologic; D000941:Antigens; D016827:CD8 Antigens; D004731:Endotoxins; D009113:Muramidase