Antigen-specific dose-dependent system for the study of an inheritable and reversible phenotype in mouse CD4+ T cells.
The transgenic T-cell receptor in mouse TEa CD4+ lymphocytes recognizes an endogenous peptide, Ealpha52-68, presented in the context of the major histocompatibility complex class II molecule I-Ab. In response to an optimal peptide concentration TEa cells enter the cell cycle and proliferate. However, a single exposure to high doses of the specific peptide diminished cell expansion upon subsequent restimulation. This hyporesponsive, or anergic, phenotype can still be detected after multiple restimulations indicating that the hyporesponsiveness persists despite cell division and it was inherited by daughter cells. Furthermore, we demonstrated that this hypoproliferative response is associated with high p27Kip1 and cyclin E protein levels, and reduced intracellular interleukin-2 (IL-2) expression. Addition of exogenous IL-2 was required to reset p27Kip1 levels in the progeny derived from hyporesponsive TEa cells. Thus, we have established antigen dose-dependent induction of a reversible, inheritable (i.e. epigenetic) phenotype and we have identified at least three components of the network of interactions: p27Kip1 cyclin E, and IL-2 expression.
Firpo
Eduardo J
EJ
Cell Systems Initiative, Department of Bioengineering, Howard Hughes Medical Institute, School of Medicine, University of Washington, Seattle, WA 98195, USA.
Kong
Raymond K
RK
Zhou
Qinghong
Q
Rudensky
Alexander Y
AY
Roberts
James M
JM
Franza
B Robert
BR
D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D018797:Cell Cycle Proteins / Q000032:analysis; D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004306:Dose-Response Relationship, Immunologic; D004791:Enzyme Inhibitors / Q000032:analysis; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry / Q000379:methods; D007376:Interleukin-2 / Q000494:pharmacology; D007399:Interphase / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics / Q000276:immunology; D008822:Mice, Transgenic / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D025521:Tumor Suppressor Proteins / Q000032:analysis
D015704:CD4 Antigens; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D000939:Epitopes; D007376:Interleukin-2; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27