Secretion of CXC chemokine IP-10 by peripheral blood mononuclear cells from healthy donors and breast cancer patients stimulated with HER-2 peptides

CXC chemokines play an important role in recruitment of T cells to the site of activation and regulation of angiogenesis, CXC chemokines are secreted by T cells stimulated with cytokines or by established cytotoxic T lymphocy te (CTL) lines at recognition of conventional antigen (Ag), but the activat ion requirements and the relationship of interferon-gamma (IFN-gamma) induc ible protein (IP-10) secretion with IFN-gamma induction in lymphocytes are still unclear. We studied the induction of IF-10 from nonadherent periphera l blood mononuclear cells (PBMC) by IFN-gamma, interleukin-12 (IL-12), and the HER-2 peptide E75, which forms a CTL-defined antigen. We found that IFN -gamma alone was a weak inducer of IF-10 in these cells, whereas IL-12 was a significantly stronger inducer of IP-10, In the presence of IL-12, the tu mor peptide E75 (HER-2, 369-377) was a stronger inducer of IF-10 than was I L-12 alone. E75 and its variants mutated at position 5 could also induce IF -10 in the absence of exogenous IL-12 or IFN-gamma, IP-10 induction by E75 required HLA-A2 presentation and B7-CD28 interactions and was partially inh ibited by blocking of CD40-CD40L interactions. These results indicate that presentation of tumor peptides to peripheral T cells can induce a fast chem okine response, which in its early phase may be higher than the IFN-gamma r esponse. This shows that the IF-10 response was independent of any early-ph ase IFN-gamma response in peripheral T cells. This may be important for und erstanding the regulation of the balance between chemoattractant chemokines (CC) and CXC chemokines by tumor Ag and may have implications for understa nding the mechanisms of polarization of T cells and conditioning of antigen -presenting cells (APC) by tumor antigens.