Antibody‐mediated delivery of antigen to chemokine receptors on antigen‐presenting cells results in enhanced CD4⁺ T cell responses

Abstract

Here, we have investigated if targeting of T cell epitopes to chemokine receptors results in improved CD4 + T cell responses. Mouse monoclonal antibodies (mAb) with ‹ L chains were targeted to various chemokine receptors expressed on human monocytes or immature dendritic cells (DC), and proliferation of cloned human, DR4-restricted CD4 + T cells specific for mouse C ‹ 40-48 was measured. When using monocytes as antigen-presenting cells, mAb specific for CCR1, CCR2, CCR5, and CXCR4 were 100-10,000-fold more efficient at inducing T cell proliferation when compared to isotype-matched control mAb on a per molecule basis. Targeting of immature DC was less effective and was only seen with anti-CCR1 and anti-CXCR4 mAb. Anti-chemokine receptors mAb required to be processed by the conventional endosomal MHC class II presentation pathway. The mAb did not induce signaling through the chemokine receptors as they failed to induce mobilization of cytosolic Ca 2+ and actin polymerization. They also failed to induce APC maturation. The results strongly suggest that chemokine receptors channel antigen into the endocytic pathway for presentation on MHC class II molecules. Targeting T cell epitopes to chemokine receptors by recombinant antibody should be a useful vaccine strategy for the induction of strong CD4 + T cell responses.

Targeting of Antigens to Activated Dendritic Cells In vivo Cures Metastatic Melanoma in Mice

“…Some successful targeting of dendritic cells using antibodies against surface receptors with broader specificity (i.e., anti-FcR or anti-chemokine receptors) has been observed previously, but the effect on immunity was rather weak (15,16). Presumably, the FcR conjugates were taken up by a variety of different lymphocytes, such as macrophages, B cells, and spleen dendritic cells, thus ''diluting'' the targeting effect (17,18).…”

“…Cancer Res 2005; 65: (15 offers the possibility not only to immunize against melanoma but also to treat tumor-bearing hosts successfully. By generating conjugates that harbor a combination of different relevant melanoma antigens, an even stronger tumor response could be induced that renders mice able to reject already existing melanomas.…”

Microarray analysis of selection lines from outbred populations to identify genes involved with nematode parasite resistance in sheep

“…Recent studies strongly suggest that CXCR4 channels the antigens into the endocytic pathway for presentation on MHC class II molecules (51). To our knowledge, there is no previous report in the literature that relates this receptor with the immune response to parasites.…”

Selection of an Antibody Library Identifies a Pathway to Induce Immunity by Targeting CD36 on Steady-State CD8α+ Dendritic Cells

“…Whether the relative ability to display peptides on class I or II products is mainly cell type or receptor regulated, however, requires further studies (10). Several other molecules like the scavenger receptor Lox-1 (11), the mannose receptor (12), some chemokine receptors (13,14), and TLRs (15,16) have been tested for their potential in immunotherapy. A critical lesson from all of these studies is that some receptors (4,5,11,12), but not others (16,17), require the addition of a DC maturation signal to induce protective immunity.…”