Enhancement of MHC class II-restricted responses by receptor-mediated uptake of peptide antigens.
Peptides, either as altered peptide ligands, competitors, or vaccines, offer an outstanding potential for regulating immune responses because of their exquisite specificity. However, a major problem associated with peptide therapies is that they are poorly taken up by APCs. Because of poor bioavailability, high concentrations and repeated treatments are required for peptide therapies in vivo. To circumvent this problem, we tested whether covalently coupling a peptide T cell determinant, OVA(323-339), to transferrin (Tf) enhances APC uptake and presentation as monitored by Th cell activation. Functional analysis of the Tf-peptide conjugates revealed that the conjugates were presented 10,000- and 100-fold more effectively by B cells than intact Ag and free peptide, respectively. Furthermore, we demonstrate that the Tf-peptide conjugates are taken up by B cells through a receptor-mediated process and subsequently delivered to the lysosomal compartment. Using an adoptive transfer assay, we show that that the Tf-peptide complexes are 100-fold more effective in vivo than the free peptide in activating CD4(+) T cells by following an early activation marker, CD69. Our results demonstrate that coupling peptides to Tf enhances peptide presentation, thereby making it possible to take full advantage of peptide-specific therapies in modulating T cell responses.
Department of Pathology, University of Alabama, Birmingham 35294, USA.
Lolita
L
Zaliauskiene
Sunghyun
S
Kang
Kerri
K
Sparks
Kurt R
KR
Zinn
Lisa M
LM
Schwiebert
Casey T
CT
Weaver
James F
JF
Collawn
D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002403:Cathepsins / Q000276:immunology / Q000378:metabolism; D002451:Cell Compartmentation / Q000276:immunology; D002460:Cell Line; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage; D006367:HeLa Cells; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D006801:Humans; D007275:Injections, Intravenous; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D011990:Receptors, Transferrin / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D014168:Transferrin / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; C111390:OVA 323-339; D010446:Peptide Fragments; D011990:Receptors, Transferrin; D014168:Transferrin; D010047:Ovalbumin; D002403:Cathepsins; C028217:cathepsin S