Evolution of antigen-specific T cell receptors in vivo: preimmune and antigen-driven selection of preferred complementarity-determining region 3 (CDR3) motifs.
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 Valpha11(+)Vbeta3(+) Th (70%) express a critical complementarity-determining region 3 (CDR3) residue (glutamic acid at TCR-alpha93) associated with PCC peptide contact. Over the first 5 d of the primary response, PCC-responsive Valpha11(+)Vbeta3(+) 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.
McHeyzer-Williams
L J
LJ
Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA. mchey002@acpub.duke.edu
Panus
J F
JF
Mikszta
J A
JA
McHeyzer-Williams
M G
MG
D000818:Animals; D001483:Base Sequence; D010856:Columbidae; D022801:Complementarity Determining Regions; D003574:Cytochrome c Group / Q000276:immunology; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D019143:Evolution, Molecular; D007137:Immunoglobulin alpha-Chains / Q000235:genetics; D007156:Immunologic Memory; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D012641:Selection, Genetic; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D022801:Complementarity Determining Regions; D003574:Cytochrome c Group; D017931:DNA Primers; D018076:DNA, Complementary; D007137:Immunoglobulin alpha-Chains; D011948:Receptors, Antigen, T-Cell