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 hist ocompatibility complex class II-restricted murine response to pigeon cytoch rome c (PCC), we provide evidence for both preimmune and Ag-driven selectio n in the evolution of Ag-specific immunity in vivo. Before antigenic challe nge, most V alpha 11(+)V beta 3(+) Th (70%) express a critical complementar ity-determining region 3 (CDR3) residue (glutamic acid at TCR-alpha 93) ass ociated with PCC peptide contact. Over the first 5 d of the primary respons e, PCC-responsive V alpha 11(+)V beta 3(+) Th expressing eight preferred CD R3 features are rapidly selected in vivo. Clonal dominance is further propa gated through selective expansion of the PCC-specific cells with T cell rec eptor (TCR) of the "best fit." Ag-driven selection is complete before signi ficant emergence of the germinal center reaction. These data argue that thy mic selection shapes TCR-alpha V region bias in the preimmune repertoire; h owever, Ag itself and the nongerminal center microenvironment drive the sel ective expansion of clones with preferred TCR that dominate the response to Ag in vivo.