Human CD14 is an efficient target for recombinant immunoglobulin vaccine constructs that deliver T cell epitopes.
It has been shown in the mouse that recombinant immunoglobulin (Ig) molecules with T cell epitopes inserted into the constant domain (Troybodies) can target antigen-presenting cells (APC) for efficient delivery of T cell epitopes. Here, we have extended the Troybody concept to human applications. Moreover, we show that a receptor of innate immunity, CD14, which is a part of the lipopolysaccharide receptor complex on monocyte APC, is an efficient target. For construction of CD14-specific Troybodies, we used rearranged variable(diversity)joining regions cloned from the 3C10 mouse B cell hybridoma. As a model T cell epitope, amino acids 40-48 of mouse Ckappa, presented on human leukocyte antigen-DR4, were inserted into a loop connecting beta-strands in C(H)1 of human gamma3. In the presence of monocytes, CD14-specific Troybodies were >100 times as efficient as a nontargeting control antibody (Ab) at stimulating Ckappa(40-48)-specific/DR4-restricted T cells. Presentation was dependent on the conventional processing pathway for presentation on major histocompatibility complex (MHC) class II molecules. Enhanced presentation of the Ckappa epitope was most likely a result of increased loading of MHC class II molecules, as the CD14-specific monoclonal Ab 3C10 did not induce maturation of the APC. The results show that CD14, a receptor of innate immunity, may be a promising target of recombinant Ig-based vaccines for elicitation of T cell responses in humans.
Tunheim
Gro
G
University of Oslo and Rikshospitalet University Hospital, N-0027 Oslo, Norway. gro.tunheim@medisin.uio.no
Schjetne
Karoline W
KW
Fredriksen
Agnete B
AB
Sandlie
Inger
I
Bogen
Bjarne
B
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D007111:Immunity, Cellular / Q000276:immunology; D007145:Immunoglobulin kappa-Chains / Q000276:immunology; D007136:Immunoglobulins / Q000276:immunology*; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014612:Vaccines / Q000276:immunology*
D000911:Antibodies, Monoclonal; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D007145:Immunoglobulin kappa-Chains; D007136:Immunoglobulins; D018950:Lipopolysaccharide Receptors; D011993:Recombinant Fusion Proteins; D014612:Vaccines