Karoline W. Schjetne

An ideal vaccine for induction of CD4⁺ T cell responses should induce local inflammation, maturation of APC, and peptide loading of MHC class II molecules. Ligation of Toll-like receptor (TLR) 2 provides the first two of these three criteria. We have studied whether targeting of TLR2 results in loading of MHC class II molecules and enhancement of CD4⁺ T cell responses. To dissociate MHC class II presentation from APC maturation, we have used an antagonistic, mouse anti-human TLR2 mAb (TL2.1) as ligand and measured proliferation of a mouse Cκ-specific human CD4⁺ T cell clone. TL2.1 mAb was 100-1000 times more efficiently presented by APC compared with isotype-matched control mAb. Moreover, TL2.1 mAb was internalized into endosomes and processed by the conventional MHC class II pathway. This novel function of TLR2 represents a link between innate and adaptive immunity and indicates that TLR2 could be a promising target for vaccines.

In vaccine development, a major objective is to induce strong, specific T cell responses. This might be obtained by targeting antigen to cell surface molecules that efficiently channel the antigen into endocytic compartments for loading of MHC molecules. Antibodies have been used to deliver antigen; however, it is important to define optimal targets on antigen‐presenting cells (APC) for efficient delivery. For this purpose, we have established a T cell readout that can be used to screen large numbers of different mAb for their ability to load MHC class II molecules. The novel human CD4⁺ T cell clone is specific for mouse Ig C_κ (40–48) and restricted by HLA‐DR4 (DRA1,B1*0401). DR4 apparently presents both mouse and human C_κ 40–48, but there is no cross‐reaction at the T cell level. B cells from DR4 transgenic mice spontaneously process and present the mouse C_κ peptide. The mouse C_κ‐specific T cell readout was used to demonstrate that mouse mAb specific for human dendritic cell (DC)‐specific ICAM‐grabbing non‐integrin (DC‐SIGN), a novel DC‐specific molecule, were 10‐ to 1000‐fold more potent at inducing κ‐specific human CD4⁺ T cell proliferation compared to control mAb. Consistent with this finding, DC‐SIGN‐specific mAb were rapidly internalized upon binding and found in intracellular vesicles. These results strongly argue that DC‐SIGN‐specific mAb are channeled into the MHC class II presentation pathway. Thus, DC‐SIGN could be an efficient target for antibody‐mediated delivery of T cell epitopes in vaccine development.