T-cell tolerance induced by repeated antigen stimulation: selective loss of Foxp3- conventional CD4 T cells and induction of CD4 T-cell anergy.
Repeated immunization of mice with bacterial superantigens induces extensive deletion and anergy of reactive CD4 T cells. Here we report that the in vitro proliferation anergy of CD4 T cells from TCR transgenic mice immunized three times with staphylococcal enterotoxin B (SEB) (3 x SEB) is partially due to an increased frequency of Foxp3(+) CD4 T cells. Importantly, reduced number of conventional CD25(-) Foxp3(-) cells, rather than conversion of such cells to Foxp3(+) cells, was the cause of that increase and was also seen in mice repeatedly immunized with OVA (3 x OVA) and OVA-peptide (OVAp) (3 x OVAp). Cell-transfer experiments revealed profound but transient anergy of CD4 T cells isolated from 3 x OVAp and 3x SEB mice. However, the in vivo anergy was CD4 T-cell autonomous and independent of Foxp3(+) Treg. Finally, proliferation of transferred CD4 T cells was inhibited in repeatedly immunized mice but inhibition was lost when transfer was delayed, despite the maintenance of elevated frequency of Foxp3(+) cells. These data provide important implications for Foxp3(+) cell-mediated tolerance in situations of repeated antigen exposure such as human persistent infections.
Eroukhmanoff
Lena
L
Section for Immunology, Lund University, Lund, Sweden.
Oderup
Cecilia
C
Ivars
Fredrik
F
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D017635:Clonal Anergy / Q000276:immunology*; D004768:Enterotoxins / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000276:immunology*; D007114:Immunization; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D018089:Superantigens / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D004768:Enterotoxins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018089:Superantigens; C031818:enterotoxin B, staphylococcal; D010047:Ovalbumin