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* Dipartimento di Scienze Cliniche e Biologiche, University of Torino, Torino, Italy;
Institute of General Pathology, Catholic University Sacro Cuore, Rome, Italy; and
Molecular Biotechnology Center, University of Torino, Torino, Italy
Central tolerance to tumor-associated Ags is an immune-escape mechanism that significantly limits the TCR repertoires available for tumor eradication. The repertoires expanded in wild-type BALB/c and rat-HER-2/neu (rHER-2) transgenic BALB-neuT mice following DNA immunization against rHER-2 were compared by spectratyping the variable (V)
and the joining (J) CDR 3. Following immunization, BALB/c mice raised a strong response. Every mouse used one or more CD8+ T cell rearrangements of the V9-J1.2 segments characterized by distinct length of the CDR3 and specific for 63-71 or 1206-1214 rHER-2 peptides. In addition, two CD4+ T cell rearrangements recurred in >50% of mice. Instead, BALB-neuT mice displayed a limited response to rHER-2. Their repertoire is smaller and uses different rearrangements confined to CD4+ T cells. Thus, central tolerance in BALB-neuT mice acts by silencing the BALB/c mice self-reactive repertoire and reducing the size of the CD8+ T cell component. CD8+ and CD4+ T cells from both wild-type and transgenic mice home to tumors. This definition of the T cell repertoires available is critical to the designing of immunological maneuvers able to elicit an effective immune reaction against HER-2-driven carcinogenesis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from Italian Association for Cancer Research, the Italian Ministries for the Universities and Health, National Multiple Sclerosis Society (Grant RG 3339-A-1), the University of Torino, Compagnia di San Paolo, Torino, and the Center of Excellence on Aging, University of Chieti, Italy.
2 Address correspondence and reprint requests to Dr. Federica Cavallo, Department of Clinical and Biological Sciences, Ospedale san Luigi Gonzaga, 10043 Orbassano, Italy. E-mail address: federica.cavallo{at}unito.it
3 Abbreviations used in this paper: WT, wild type; rHER-2, rat HER-2/neu; BALB-neuT mice, rHER-2 transgenic BALB/c mice; MMTV, mouse mammary tumor virus; EC-TMneu, extracellular and transmembrane domains of the protein product of rHER-2; RSI, rate of stimulation index; V, variable; J, joining; CDR, complementarity-determining region; TAA, tumor-associated Ag.
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