VIRAL AND BACTERIAL-INFECTIONS INTERFERE WITH PERIPHERAL TOLERANCE INDUCTION AND ACTIVATE CD8(-CELLS TO CAUSE IMMUNOPATHOLOGY() T)

We studied the impact of various infectious and proinflammatory agents on the induction of peripheral T cell tolerance. Adoptive transfer of CD8(+) T cells from lymphocytic choriomeningitis virus (LCMV) T cell receptor transgenic mice into LCMV antigen transgenic mice expressing the LCMV glycoprotein epitope (gp) 33-41 under control of a major hist ocompatibility complex class I promoter led to efficient induction of peripheral tolerance after a period of transient activation. Ii, howev er, the recipient mice were challenged with viral or bacterial infecti ons or proinflammatory agents (Lipopolysaccharide or Poly:IC) early af ter cell transfer, tolerance induction was prevented and instead, CD8( +) T cell activation leading to vigorous expansion and generation of c ytolytic activity ensued. This became manifest in significant immunopa thology mainly involving destruction of the splenic architecture and l ysis of antigen-expressing lymphocyte and macrophage populations. Impo rtant parameters involved in the activation of host-reactive T cells b y nonspecific infectious agents included the presence, localization, a nd quantity of the specific transgene-encoded self-antigen; in contras t, CD4(+) T cells were not required. In mice surviving the acute phase , the transferred CD8(+) T cells persisted at high levels in an anergi c state; they were unable to generate cytolytic activity in vitro or t o control LCMV infection in vivo. These results impinge on our underst anding of the role of infectious agents in graft verus host reactions towards minor histocompatibility antigens.