Rejection?Repertoire Be Exploited for Tumor Can the Low-Avidity Self-Specific T Cell

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 (cid:1) 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 (cid:1) 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 (cid:1) T cells. In addition, cultured memory NP-specific T cells require (cid:1) 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. The Journal of Immunology, 2 (cid:3) 10 3 cells were added per well. To block NK cell activity, a 50-fold excess of unla-beled YAC cells was added to the wells. Per target, spontaneous release was measured by incubating the labeled cells in medium alone. Maximum release was measured by incubating the labeled cells in 2% Triton X-100. After a 5-h incubation at 37°C, 25 (cid:1) l of supernatant from triplicate cultures was harvested in Luma plates (Packard Instrument, Meriden, CT) and counted in a TopCount Microplate Scintillation Counter (Packard Instru-ment). The percentage of specific 51 Cr release was calculated as a ratio of 100 (cid:3) (cpm experimental release (cid:4) cpm spontaneous release)/(cpm 2% Triton X-100 release (cid:4) cpm spontaneous release).