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

Abstract

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 Vα11+Vβ3+ Th (70%) express a critical complementarity-determining region 3 (CDR3) residue (glutamic acid at TCR-α93) associated with PCC peptide contact. Over the first 5 d of the primary response, PCC-responsive Vα11+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-α 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.

Role of Ox40 Signals in Coordinating Cd4 T Cell Selection, Migration, and Cytokine Differentiation in T Helper (Th)1 and Th2 Cells

“…As CD28 and OX40 signals are synergistic, this would provide a mechanism to selectively expand high-affinity CD4 cells and favor their migration to B follicles. This model of costimulation explains experimental data that shows that high-affinity CD4 T cells are expanded in the T zone 23 and then selectively exported to B follicles to foster GCs 24.…”

“…The CD4 T cell response to pigeon cytochrome C model is well characterized and would provide an excellent system in which to test this possible mechanism 11 23. It would be very interesting to establish whether the impaired CD4 T cell memory reported here in OX40L-deficient mice was linked with a failure to efficiently expand high-affinity CD4 T cells and export them to B follicles.…”

Antigen-Experienced CD4 T Cells Display a Reduced Capacity for Clonal Expansion In Vivo That Is Imposed by Factors Present in the Immune Host

“…This phenomenon is also apparent in the work of McHeyzer-Williams and colleagues (22,23), who showed that moth cytochrome-specific naive T cells in normal mice expand 300-fold during the primary response, whereas Ag-experienced T cells of the same specificity expanded 30-fold in response to secondary challenge. Similarly, Kerksiek et al (24) and Kedl et al (25) showed that certain Ag-specific CD8 T cells undergo extensive clonal expansion after primary, but not secondary, stimulation.…”

Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion

“…These data support the notion of selective clonotype expansion within the TRBV29 + K b NS2 114 -specific population. Previous studies with TCR Tg T cells indicate that such selection reflects differing TCR avidity profiles (37,43). As such, enrichment of TRBV bias from the naive into the immune repertoire is presumably due to the preferential selection/proliferation of CTLps with "optimal-fit" TCRs (37,43,44).…”