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© The Rockefeller University Press, 0022-1007/1999/6/1823/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 11, June 7, 1999 1823-1838

Articles

Evolution of Antigen-specific T Cell Receptors In Vivo: Preimmune and Antigen-driven Selection of Preferred Complementarity-determining Region 3 (CDR3) Motifs

Louise J. McHeyzer-Williams, Joanne Fanelli Panus, John A. Mikszta, and Michael G. McHeyzer-Williams

From the Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710

Antigen (Ag)-driven selection of helper T cells (Th) in normal animals has been difficult to study and remains poorly understood. Using the major histocompatibility complex class II– restricted murine response to pigeon cytochrome c (PCC), we provide evidence for both preimmune and Ag-driven selection in the evolution of Ag-specific immunity in vivo. Before antigenic challenge, most V{alpha}11+Vβ3+ Th (70%) express a critical complementarity-determining region 3 (CDR3) residue (glutamic acid at TCR-{alpha}93) associated with PCC peptide contact. Over the first 5 d of the primary response, PCC-responsive V{alpha}11+Vβ3+ Th expressing eight preferred CDR3 features are rapidly selected in vivo. Clonal dominance is further propagated through selective expansion of the PCC-specific cells with T cell receptor (TCR) of the "best fit." Ag-driven selection is complete before significant emergence of the germinal center reaction. These data argue that thymic selection shapes TCR-{alpha} V region bias in the preimmune repertoire; however, Ag itself and the nongerminal center microenvironment drive the selective expansion of clones with preferred TCR that dominate the response to Ag in vivo.

Key Words: immunologic memory • clonal maturation • antigen-specific immunity • helper T cells • T cell receptor

Address correspondence to Michael G. McHeyzer-Williams, Duke University Medical Center, Department of Immunology, Rm. 316 Jones Bldg., Research Dr., Durham, NC 27710. Phone: 919-613-7821; Fax: 919-684-8982; E-mail: mchey002{at}acpub.duke.edu

J.A. Mikszta was a recipient of a National Research Service Award fellowship. This work was supported by an Arthritis Foundation Biomedical Sciences Grant and National Institutes of Health grant AI40215.

Abbreviations used: aa, amino acids; CDR3, complementarity-determining region 3; GC, germinal center; LSCM, laser scanning confocal microscopic; MCC, moth cytochrome c; PCC, pigeon cytochrome c; PI, propidium iodide; RT, reverse transcriptase; TR, Texas Red.


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