Can the low-avidity self-specific T cell repertoire be exploited for tumor rejection?
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 approximately 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.
Cordaro
Tanina A
TA
Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
de Visser
Karin E
KE
Tirion
Felicia H
FH
Schumacher
Ton N M
TN
Kruisbeek
Ada M
AM
D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D009980:Influenza A virus / Q000276:immunology; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000096:biosynthesis / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D012878:Skin Neoplasms / Q000276:immunology / Q000378:metabolism; D013045:Species Specificity; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014758:Viral Core Proteins / Q000096:biosynthesis / Q000276:immunology
D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D007376:Interleukin-2; D010446:Peptide Fragments; D014758:Viral Core Proteins; C102366:nucleoprotein (366-374), influenza virus; D007371:Interferon-gamma