[show abstract][hide abstract] ABSTRACT: 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.
The Journal of Immunology 02/2002; 168(2):651-60. · 5.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: It is well established that expression of self antigens results in the deletion of the functional high-avidity self-specific T cell repertoire. Due to the low frequency of naturally occurring low-avidity self-specific T cells, a detailed evaluation of their ability to survive and differentiate into effector and memory populations in vivo has yet to be obtained. We here employ tetramer technology to characterize and determine the in vivo fate of a self-specific CD8+ T cell population specific for a ubiquitously expressed T cell epitope. We find that in influenza nucleoprotein (NP)-transgenic mice (B10NP mice) an oligoclonal population of NP366 – 374-specific T cells can be triggered by live influenza virus exposure. The main hallmark of this self-specific T cell population is its diminished avidity for the tetrameric MHC / NP peptide complex. These low-avidity T cells are not deleted and do not down-regulate their antigen or CD8 receptors, and exhibit cytolytic activity towards tumor cells expressing NP endogenously. Strikingly, a secondary influenza infection generates a typical memory response in the low-avidity repertoire. The observation that low-avidity T cells persist in vivo and can differentiate into memory T cells underscores their potential role in anti-tumor immunity.
European Journal of Immunology 05/2000; 30(5):1458 - 1468. · 4.97 Impact Factor