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Recent studies have demonstrated that [CD4.sup.+] T cells can efficiently reject MHC-II-negative tumors. This requires indirect presentation of tumor-associated antigens on surrounding antigen-presenting cells. We hypothesized that intercellular transfer of proteins is not the sole consequence of cell death-mediated protein release, but depends on heat-shock cognate protein 70 (HSC70) and its KFERQ-like binding motif on substrate proteins. Using human Y chromosome antigen DBY, we showed that mutation of one of its 2 putative binding motifs markedly diminished T cell activation after indirect presentation and reduced protein-protein interaction with HSC70. Intercellular antigen transfer was shown to be independent of cell-cell contact, but relied on engulfment within secreted microvesicles. In vivo, alterations of the homologous KFERQ-like motif in murine DBY hampered tumor rejection, T cell activation, and migration into the tumor and substantially impaired survival. Collectively, we show that intercellular antigen transfer of DBY is tightly regulated via binding to HSC70 and that this mechanism influences recognition and rejection of MHC-II-negative tumors in vivo., Introduction [CD4.sup.+] T cells play a central role in orchestrating innate and adaptive immune responses. Upon recognition of their cognate antigen in MHC-II molecules, [CD4.sup.+] T cells become activated and [...]

Patients with hematological malignancies can be successfully treated with HLA-matched T cell-depleted allogeneic stem cell transplantation (alIoSCT) and subsequent donor lymphocyte infusions (DLIs). The efficacy of DLI is mediated by donor T cells recognizing minor histocompatibility antigens (mHags) on malignant recipient cells. Because HLA class II molecules are predominantly expressed on hematopoietic cells, mHag-specific [CD4.sup.+] T cells may selectively mediate graft versus leukemia (GvL) reactivity without graft versus host disease (GvHD). In this study, we used a recombinant bacteria cDNA library for the identification of the first autosomal HLA class II (HLA-DQBl*0603)-restricted mHag LBPI4K2B-1S encoded by the broadly expressed phosphatidylinositol 4-kinase type II [beta] gene. A polyclonal [CD4.sup.+] T cell response against LB-PI4K2B-1S was demonstrated in a patient with relapsed chronic myeloid leukemia (CML) who responded to DLI after HLA-matched alIoSCT. LB-PI4K2B-1S-specific [CD4.sup.+] T cells recognized and lysed the [CD34.sup.+] CML cells of the patient and other leukemic cells as well as high HLA-DQ-expressing normal hematopoietic cells. HLA-DQ expression on normal cells of nonhematopoietic origin was moderately up-regulated by IFN-[gamma], and not sufficient for T cell recognition. We hypothesize that LB-PI4K2B-1S-specific [CD4.sup.+] T cells contributed to the antitumor response by both directly eliminating malignant cells as effector cells and stimulating [CD8.sup.+] T cell immunity as helper cells. donor lymphocyte infusions | hematological malignancies | immunotherapy | stem cell transplantation | T lymphocytes