title: Clonotype-specific avidity influences the dynamics and hierarchy of virus-specific regulatory and effector CD4(+) T-cell responses.
abstract: 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.
authors: Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, MD, USA.
authors: Jie
authors: J
authors: Liu
authors: Shirley
authors: S
authors: Cao
authors: Gretchen
authors: G
authors: Peppers
authors: Sung-Han
authors: SH
authors: Kim
authors: Barney S
authors: BS
authors: Graham
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D002999:Clone Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000276:immunology* / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000821:virology
chemical_list: D018984:Epitopes, T-Lymphocyte; D016693:Receptors, Antigen, T-Cell, alpha-beta
keywords: Precursor frequency; Respiratory syncytial virus; T-cell hierarchy; T-cell receptor (TCR) avidity; Treg cell