CD4+ CD25+ regulatory T cell repertoire formation in response to varying expression of a neo-self-antigen.
We have examined the development of self-peptide-specific CD4+ CD25+ regulatory T cells in lineages of transgenic mice that express the influenza virus PR8 hemagglutinin (HA) under the control of several different promoters (HA transgenic mice). By mating these lineages with TS1-transgenic mice expressing a TCR that recognizes the major I-E(d)-restricted determinant from HA (site 1 (S1)), we show that S1-specific T cells undergo selection to become CD4+ CD25+ regulatory T cells in each of the lineages, although in varying numbers. In some lineages, S1-specific CD4+ CD25+ regulatory T cells are highly abundant; indeed, TS1xHA-transgenic mice can contain as many S1-specific CD4+ T cells as are present in TS1 mice, which do not express the neo-self HA. In another lineage, however, S1-specific thymocytes are subjected to more extensive deletion and far fewer S1-specific CD4+ CD25+ regulatory T cells accumulate in the periphery. We show that radioresistant stromal cells can direct both deletion and CD4+ CD25+ regulatory T cell selection of S1-specific thymocytes. Interestingly, even though their numbers can vary, the S1-specific CD4+ CD25+ regulatory T cells in all cases coexist with clonally related CD4+ CD25- T cells that lack regulatory function. These findings show that the formation of the CD4+ CD25+ regulatory T cell repertoire is sensitive to variations in the expression of self-peptides.
Lerman
Melissa A
MA
Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104.
Larkin
Joseph
J
Cozzo
Cristina
C
Jordan
Martha S
MS
Caton
Andrew J
AJ
D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015704:CD4 Antigens / Q000032:analysis*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011836:Radiation Tolerance; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000032:analysis*; D013601:T-Lymphocytes / Q000502:physiology*
D001324:Autoantigens; D015704:CD4 Antigens; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2