A Large Number of T Lymphocytes Recognize Moloney-Murine Leukemia Virus-Induced Antigens, but a Few Mediate Long-Lasting Tumor Immunosurveillance

Abstract

The CD8+ T cell response to Moloney-murine leukemia virus (M-MuLV)-induced Ags is almost entirely dominated by the exclusive expansion of lymphocytes that use preferential TCRVβ chain rearrangements. In mice lacking T cells expressing these TCRVβ, we demonstrate that alternative TCRVβ can substitute for the lack of the dominant TCRVβ in the H-2-restricted M-MuLV Ag recognition. We show that, at least for the H-2b-restricted response, the shift of TCR usage is not related to a variation of the immunodominant M-MuLV epitope recognition. After virus immunization, all the potentially M-MuLV-reactive lymphocytes are primed, but only the deletion of dominant Vβ rescues the alternative Vβ response. The mechanism of clonal T cell “immunodomination” that guides the preferential Vβ expansion is likely the result of a proliferative advantage of T cells expressing dominant Vβ, due to differences in TCR affinity and/or cosignal requirements. In this regard, a CD8 involvement is strictly required for the virus-specific cytotoxic activity of CTL expressing alternative, but not dominant, Vβ gene rearrangements. The ability of T cells expressing alternative TCRVβ rearrangements to mediate tumor protection was evaluated by a challenge with M-MuLV tumor cells. Although T cells expressing alternative Vβ chains were activated and expanded, they were not able to control tumor growth in a long-lasting manner due to their incapacity of conversion and accumulation in the T central memory pool.

Elimination of Immunodominant Epitopes from Multispecific DNA-Based Vaccines Allows Induction of CD8 T Cells That Have a Striking Antiviral Potential

“…Different factors have been proposed to contribute to immunodominance. These include: competition between responding T cells (47) or T cells and APCs (55), inefficient Ag processing (51), or peptide binding to MHC class I molecules (41,48,56), only a few specific precursors in the naive T cell pool for the subdominant epitopes or high T cell precursor frequencies specific for an immunodominant epitope (57,58), competition between MHC class I alleles for cell surface expression (49), the kinetics of viral protein expression (50), and regulatory T cells that selectively suppress certain responses (59 (35). This may be related to specific effects of Hsp73, e.g., enhanced expression of Ags, induction of cross-priming (34,60).…”

Host-derived CD8+ dendritic cells are required for induction of optimal graft-versus-tumor responses after experimental allogeneic bone marrow transplantation

“…18 Only the allogeneic Batf3 2/2 animals demonstrated reduced GVT responses against EL-4 tumors ( Figure 2C). 16,17 which is present only in the tumor cells and not in the host tissues. The frequency (2.34% 6 0.67%; n 5 6) and absolute number (0.08 6 0.04 3 10 6 ) of gagtetramer 1 CD8 1 T cells from CD8 1 DC-transferred animals were significantly higher than in those animals that received either no DC transfer (1.30% 6 0.52%; P 5 .26; 0.007 6 0.002 3 10 6 ; P 5 .04; n 5 6) or those animals that received CD8…”

“…6 MBL-2 is a Moloney murine leukemia virus-induced T-cell lymphoma, 15,16 and EL-4 is a chemically induced T-cell lymphoma. 17 Both are of B6 origin (H-2 b ) and were extensively used as models of acute leukemia and lymphoma.…”

“…9 To simultaneously evaluate GVT responses, we infused 2 3 10 4 MBL-2 (H-2 b ) tumor cells at the time of transplantation. MBL-2 is a Moloney murine sarcoma virus/Moloney murine leukemia virusinduced T-cell lymphoma 16,17 that is syngeneic to the host B6 mouse and is uniformly lethal at a dose of 5 3 10 3 cells in a syngeneic setting. 6 MBL-2 cells express the immune-dominant TSA, the gagencoded protein, 16 in addition to the miHAs that can be recognized by the donor C3H.sw CD8 1 T cells.…”

“…MBL-2 is a Moloney murine sarcoma virus/Moloney murine leukemia virusinduced T-cell lymphoma 16,17 that is syngeneic to the host B6 mouse and is uniformly lethal at a dose of 5 3 10 3 cells in a syngeneic setting. 6 MBL-2 cells express the immune-dominant TSA, the gagencoded protein, 16 in addition to the miHAs that can be recognized by the donor C3H.sw CD8 1 T cells. 6 All of the syngeneic animals showed no signs of GVHD and died of tumor burden, demonstrating that TSA responses alone are insufficient for elimination of the tumor cells in these models (Figure 2A).…”