Priming CBA mice (H-2k) with infectious ectromelia virus (EV) and C3H mice (H-2k) with noninfectious vaccinia virus (VAC) resulted in a transient virus-specific splenic cytotoxic T lymphocyte (CTL) response followed by persisting CTL memory. When unfractionated spleen cells from these mice were cultured with mitomycin-C-treated stimulator L fibroblasts (H-2k) exposed previously to the homologous noninfectious virus, potent secondary (2°) virus-specific CTL were induced. CTL induction was not affected by depleting the responders of phagocytic and/or adherent cells (presumed to be macrophages) if either virus was presented on L cells. However, only unfractionated responders yielded 2° CTL when cultured with free EV or VAC, indicating that fibroblasts could substitute for responder macrophages as antigen-presenting cells. The failure of virus to induce 2° CTL when presented on either allogeneic fibroblasts or Sepharose provided clear evidence that triggering of CTL precursors required the recognition of antigen in some closely linked association with a “self” marker. This requirement also held for stimulating the responders to undergo virus-specific proliferative responses although proliferation was not a prerequisite for 2° CTL induction.

By exposing L cells to defined numbers of purified noninfectious VAC for only 10 min and then after increasing intervals fixing them with glutaraldehyde, it was shown that viral adsorption alone was necessary for the cells to become capable of both stimulating the induction of 2° CTL and inhibiting competitively their lytic activity. After adsorption, this dual capability of the cells increased at a rate that correlated inversely with the concentration of virions to which they were initially exposed. Thus, the stimulator or competitor efficacy of cells exposed to a poxvirion multiplicity of 5000 to 10,000 for 10 min was reached 90 min later by cells exposed to a multiplicity of 50 to 100.

Collectively, these experiments demonstrate that only a brief exposure of host cell membranes to intact poxvirions is required to form the antigenic configuration recognized by poxvirus-specific CTL or their precursors. Since this event can occur under conditions that do not favor viral modification of native host cell membrane antigens, it supports the concept that antigen recognition occurs through T lymphocyte receptors with separate specificities for “self” and viral determinants.

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