Clonotype-specific avidity influences the dynamics and hierarchy of virus-specific regulatory and effector CD4(+) T-cell responses.

A key component of immunity against viruses, CD4(+) T cells expand and differentiate into functional subsets upon primary infection, where effector (Teff) cells facilitate infection control and regulatory (Treg) cells mitigate immunopathology. After secondary infection, Teff cells mount a robust response from the memory pool. Here, we show that Treg-cell responses are diminished upon secondary infection, and Treg-cell response dynamics are associated more with T-cell receptors (TCRs) repertoire and avidity than with epitope specificity. In the murine model, the IA(b) M209 epitope of respiratory syncytial virus is recognized by both CD4(+) Treg and Teff cells, while the IA(b) M226 epitope is recognized almost exclusively by CD4(+) Teff cells expressing high avidity TCR Vβ8.1/8.2 and dominating the CD4(+) T-cell response during primary and secondary infections. IA(b) M209 -Teff cells express relatively low avidity TCRs during early primary infection, but high avidity TCR Vβ7-expressing IA(b) M209 -Teff cells emerge during the late phase, and become dominant after secondary infection. The emerging high avidity IA(b) M209 -Teff cells outcompete IA(b) M209 -Treg cells that share the same epitope, but have low avidity and are restricted to TCR Vβ2 and Vβ6 subpopulations. These data indicate that MHC-peptide-TCR interactions can produce different kinetic and functional profiles in CD4(+) T-cell populations even when responding to the same epitope.