Characterization of CD8(+) T lymphocytes that persist after peripheral tolerance to a self antigen expressed in the pancreas

As a result of expression of the influenza hemagglutinin (HA) in the pancre atic islets, the repertoire of HA-specific CD8(+) T lymphocytes in InsHA tr ansgenic mice (D2 mice expressing the HA transgene under control of the rat insulin promoter) is comprised of cells that are less responsive to cognat e Ag than are HA-specific CD8(+) T lymphocytes from conventional mice. Prev ious studies of tolerance induction involving TCR transgenic T lymphocytes suggested that a variety of different mechanisms can reduce acidity for Ag, including altered cell surface expression of molecules involved in Ag reco gnition and a deficiency in signaling through the TCR complex, To determine which, if any, of these mechanisms pertain to CD8(+) T lymphocytes within a conventional repertoire, HA-specific CD8(+) T lymphocytes from B10.D2 mic e and B10.D2 InsHA transgenic mice were compared with respect to expression of cell surface molecules, TCR gene utilization, binding of tetrameric K(d )HA complexes, lytic mechanisms, and diabetogenic potential. No evidence wa s found for reduced expression of TCR or CD8 by InsHA-derived CTL, nor was there evidence for a defect in triggering lytic activity. However, avidity differences between CD8(+) clones correlated with their ability to bind K(d )HA tetramers, These results argue that most of the K(d)HA-specific T lymph ocytes in InsHA mice are not intrinsically different from K(d)HA-specific T lymphocytes isolated from conventional animals. They simply express TCRs t hat are less avid in their binding to K(d)HA.