CD4(+) CD25(+) regulatory T cell selection.
Accumulating evidence indicates that regulatory T cells play a crucial role in preventing autoimmunity. To examine the processes by which regulatory CD4(+) T cells are produced during immune repertoire formation, we have developed transgenic mice that express the influenza virus hemagglutinin (HA) and coexpress major histocompatibility complex class II-restricted T cell receptors (TCRs) with varying affinities for the HA-derived CD4(+) T cell determinant S1. We show that interactions with a single self-peptide can induce thymocytes bearing an autoreactive TCR to undergo selection to become CD4(+) CD25(+) regulatory T cells, and that thymocytes bearing TCRs with low affinity for S1 do not undergo selection into this pathway. We show that CD4(+) thymocytes with identical specificity for the S1 self-peptide can undergo overt deletion versus abundant selection to become CD4(+) CD25(+) regulatory T cells in response to variations in expression of the S1 self-peptide in different lineages of HA transgenic mice. We also show that CD4(+) CD25(+) T cells proliferate in response to their selecting self-peptide in the periphery. Moreover, they do not proliferate in response to lymphopenia in the absence of the selecting self-peptide, reflecting a low level of expression of the high-affinity receptor for IL-7 (CD127) relative to conventional CD4(+) T cells. These studies are determining how specificity for self-peptides directs the thymic selection and peripheral expansion of CD4(+) CD25(+) regulatory T cells. Moreover, the differing responsiveness of CD4(+) CD25(+) regulatory T cells to cytokine- versus self-peptide-mediated signals may direct their accumulation to sites where the self-peptide is expressed.
Caton
Andrew J
AJ
The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104, USA. caton@wistar.upenn.edu
Cozzo
Cristina
C
Larkin
Joseph
J
Lerman
Melissa A
MA
Boesteanu
Alina
A
Jordan
Martha S
MS
D000818:Animals; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology
D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2