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Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Can self-specific T cells that have escaped intrathymic deletion be
exploited to generate antitumor immunity? To determine whether
antitumor immunity to a self-Ag for which central tolerance exists can
be generated, a mouse model is used in which a fragment of the
influenza nucleoprotein (NP) is expressed as a transgene under the
control of the H-2K promoter in C57BL/10 mice (B10NP mice). In these
mice an oligoclonal population of NP-specific T cells escapes thymic
and peripheral deletion and can be activated upon immunization. The
main hallmark of these self-specific CD8+ T cells is
diminished avidity for the pertinent MHC/peptide complex. We show in
this study that intranasal infection with influenza virus can stimulate
low-avidity NP-specific T cells to recognize and destroy NP-expressing
microtumors in the lung, but not NP-expressing tumors growing s.c. Only
a memory NP-specific CD8+ T cell response can suppress the
growth of an s.c. growing NP-expressing tumor. This delay in tumor
growth is associated with a dramatic increase in the number of
circulating NP-specific CD8+ T cells. In addition, cultured
memory NP-specific T cells require 
100-fold less Ag to induce
NP-specific lysis than primary T cells, consistent with the observation
that memory T cells have an increased avidity due to affinity
maturation. Finally, during an NP-specific memory response, substantial
numbers of low-avidity NP-specific T cells can be recovered from s.c.
growing tumors. Together, these findings indicate that, when only a
low-avidity repertoire is available to generate antitumor immunity, the
best strategy may be to enhance memory responses.
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