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Discrete T Cell Populations with Specificity for a Neo-Self-Antigen Bear Distinct Imprints of Tolerance¹

Nathan E. Standifer^2,*, Sue Stacy, Ellen Kraig^*, and Anthony J. Infante^3,*,

^* Department of Microbiology and Immunology, Department of Cellular and Structural Biology, and Department of Pediatrics, University of Texas Health Science Center, San Antonio, TX 78229

Mice expressing the Torpedo acetylcholine receptor -chain as a neo-self-Ag exhibit a reduced frequency of T cells responding to the immunodominant epitope T146–162 indicating a degree of tolerance. We characterized tolerance induction in these animals by analyzing the residual T146–162-responsive T cell population and comparing it to that of nontransgenic littermates. Using CD4^high sorting, we isolated the vast majority of Ag-reactive T cells from both strains of mice. Quantitative studies of the CD4^high populations in transgenic mice following immunization with T146–162 revealed a diminished expansion of cells expressing the canonical TCRBV6 but not other TCRBV gene segments when compared with nontransgenic littermates. In addition, CD4^high cells from transgenic mice were functionally hyporesponsive to T146–162 in terms of proliferation and cytokine secretion regardless of TCRBV gene segment use. TCR sequence analysis of transgenic V6⁺CD4^high cells revealed a reduced frequency of cells expressing a conserved motif within the TCR CDR3. Thus, the canonical T146–162 responsive, V6⁺ population demonstrates both quantitative and qualitative deficits that correlate with an altered TCR repertoire whereas the non-V6 population in transgenic mice exhibits only a reduction in peptide responsiveness, a qualitative defect. These data demonstrate that discrete autoreactive T cell populations with identical peptide/MHC specificity in Torpedo acetylcholine receptor--transgenic animals bear distinct tolerance imprints.

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 the following National Institutes of Health Grants: AI43061 (to A.J.I.), AG14557 (to E.K.), T32 Grants AG00165 and AG00205 (to S.S.), and the Nathan Shock Aging Center. Additional support was obtained from the Howard Hughes Medical Institute Research Resources Program and a fellowship from the Myasthenia Gravis Foundation of America (to S.S.).

² Current address: Benaroya Research Institute at Virginia Mason, Diabetes Program, 1201 Ninth Avenue, Seattle, WA 98101-2795.

³ Address correspondence and reprint requests to Dr. Anthony J. Infante, University of Texas Health Science Center MC7802, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. E-mail address: infantea{at}uthscsa.edu

⁴ Abbreviations used in this paper: EAMG, experimental autoimmune myasthenia gravis; AChR, acetylcholine receptor; TAChR, Torpedo AChR; LNC, lymph node cell.