Expression of the target antigen for cytotoxic T lymphocytes on adult T‐cell‐leukemia cells

Abstract

Adult T-cell-leukemia (ATL) cells were examined for susceptibility to human T-cell-leukemia virus type I (HTLV-I) tax-specific cytotoxic T lymphocytes (CTL) derived from a patient with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). These CTL efficiently killed HLA-matched leukemia cells of an ATL patient after overnight incubation. However, ATL cells immediately after isolation from the peripheral blood were only marginally susceptible to the CTL. This is not due to inappropriate expression of major-histocompatibility-complex (MHC)-class-I antigen on the leukemia cells. Addition of synthetic peptide, corresponding to the CTL epitope, to the assay enabled the CTL to kill the fresh ATL cells. Scarcity of HTLV-I antigens in the fresh ATL cells and induction of these antigens by in vitro incubation were demonstrated both on the cell surface and in the cytoplasm. Lectin stimulation augmented synthesis of HTLV-I antigens, but was not essential for the induction. The presence in the culture of human plasma containing a high titer of antibodies to HTLV-I did not affect the induction of HTLV-I expression in the ATL cells. Furthermore, significantly lower levels of HTLV-I tax mRNA were present in the fresh ATL cells than in the cultured ATL cells, whereas the levels of HTLV-I proviral tax gene did not differ among these cells. This suppression of HTLV-I transcription in fresh ATL cells accounts for resistance to the CTL, and could be a reason for the persistence of HTLV-I infection in vivo.

Overexpression of a cell adhesion molecule, TSLC1, as a possible molecular marker for acute-type adult T-cell leukemia

“…36 As shown previously, significantly lower levels of HTLV-I tax mRNA were present in the fresh ATL cells than in the cultured ATL cells. 37 Moreover, the gene expression profile easily changed under the culture conditions in vitro. Therefore, our approach to examining primary ATL should provide valuable information on molecular markers.…”

Loss of the ex vivo but not the reinducible CD8+ T-cell response to Tax in human T-cell leukemia virus type 1-infected patients with adult T-cell leukemia/lymphoma

“…Indeed, since ATLL cells have been shown to constitutively produce cytokines with immunosuppressive properties such as TGF-b, 26 IL-10, 25 and VEGF, 27 their massive proliferation in vivo could strongly impair the processes of CD8 þ T-cell proliferation and differentiation. Reduced priming of CD8 þ T cells could also be related to mechanism of immune escape developed in ATLL cells such as extinction of Tax expression [28][29][30] and/or decreased recognition of Tax epitopes due to downregulation of MHC-I expression 31 or mutations into immunodominant Tax epitopes. 21 In conclusion, we demonstrated that the anti-HTLV-1 CD8 þ T-cell response found in ATLL patients differs from that of other HTLV-1-infected individuals because CD8 þ effectors are not generated or are not functional.…”

Treatment of Adult T-cell Leukemia

“…HTLV-1 Taxspecific CTLs are capable of lysing short-term cultured ATL cells in vitro. 171 HTLV-1 Tax-specific CTLs might contribute to antitumor effects in HTLV-1 infected patients. In rat models, the antitumor effects was mediated by T-cells directed to HTLV-1 Tax.…”