| Abstract: |
A major challenge in tumor immunology is how best to activate the relatively low avidity self-specific and tumor-specific T cells that are available in the self-tolerant repertoire. To address this issue, we produced a TCR transgenic mouse expressing a class I-restricted hemagglutinin (HA)-specific TCR (clone 1 TCR) derived from a mouse that expressed HA as a self-Ag in the insulin-producing βcells of the pancreatic islets (InsHA) mice. Upon transfer of clone 1 TCR CD8+ T cells into InsHA mice, very few cells were activated by cross-presented HA, indicating that the cells were retained in InsHA mice because they ignored the presence of Ag, and not because they were functionally inactivated by anergy or tuning. Upon transfer into recipient mice in which HA is expressed at high concentrations as a tumor-associated Ag in spontaneously arising insulinomas (RIP-Tag2-HA mice), a high proportion of clone 1 cells were activated when they encountered cross-presented tumor Ag in the pancreatic lymph nodes. However, the activated cells exhibited very weak effector function and were soon tolerized. The few activated cells that did migrate to the tumor were unable to delay tumor progression. However, when HA-specific CD4 helper cells were cotransferred with clone 1 cells into RIP-Tag2-HA recipients and the mice were vaccinated with influenza, clone 1 cells were found to exert a significant / level of effector function and could delay tumor growth. This tumor model should prove of great value in identifying protocols that can optimize the function of low avidity tumor-specific T cells. |
| Keywords: |
controlled study; nonhuman; pancreatic neoplasms; pancreas; cd8 antigen; t lymphocyte; cd8-positive t-lymphocytes; animal cell; mouse; animals; mice; animal tissue; gene expression; animal experiment; animal model; cell differentiation; tumor antigen; mice, inbred c57bl; transgenic mouse; mice, transgenic; t lymphocyte receptor; immunological tolerance; antigen presentation; lymphocyte activation; antigens, neoplasm; receptors, antigen, t-cell; lymph node; cd4-positive t-lymphocytes; t-lymphocytes, cytotoxic; cell migration; autoantigen; autoantigens; insulin; tumor immunity; cytotoxicity, immunologic; tumor model; cd4 antigen; tumor growth; pancreas islet beta cell; epitopes, t-lymphocyte; concentration (parameters); influenza vaccine; cell activation; cell adhesion; clone cells; t lymphocyte activation; helper cell; insulinoma; cross-priming; mice, inbred dba; clonal anergy; hemagglutinin; hemagglutinin glycoproteins, influenza virus
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