T cell tolerance induced by histone deacetylase inhibitor is mediated by P21cip1.
MEB [n-butyrate 2-(4-morpholinyl) ethyl butyrate hydrochloride], a histone deacetylase inhibitor and G1 blocker, has been shown to induce unresponsiveness in antigen-activated Th1 cells. MEB was tested for here for its ability to inactivate naive alloantigen-specific T cells from DBA/2 and C57BL/10 mice. Since T cells from these two strains of mice have been shown to differ in their cell cycle regulation, it we hoped that this comparison would provide information concerning the role of cycle regulatory proteins in mediating MEB-induced T cell unresponsiveness. MEB inhibited proliferation in a one-way mixed lymphocyte reaction (MLR) in which spleen cells from DBA/2 mice (H-2d) or C57BL/10 mice (H-2b) were stimulated with spleen cells from C57BL/10 or DBA/2 mice, respectively. C57BL/10 responder T cells isolated from the MEB-treated primary MLR remained unresponsive to alloantigen following restimulation in a secondary MLR that did not contain MEB. T cells from DBA/2 mice were less sensitive to MEB-induced unresponsiveness and required a longer exposure or pretreatment with IL-2 to become tolerant. In all cases responsiveness to MEB-induced tolerance in the alloantigen-stimulated T cells corresponded with the levels of the cyclin-dependent kinase inhibitor p21cip1. Additional experiments showed that T cells from p21cip1-deficient mice, unlike T cells from p21cip1 wild-type littermates, were resistant to MEB-induced tolerance. These results underscore the role of p21cip1 in mediating T cell tolerance induced by the histone deacetylase inhibitor MEB.
Gilbert
Kathleen M
KM
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences/Arkansas Children's Hospital Research Institute, Little Rock 72205, USA. gilbertkathleenm@uams.edu
Boger
Susan R
SR
Price
Peter
P
Fifer
E Kim
EK
D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D019169:Jurkat Cells; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology*; D013045:Species Specificity; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000201:enzymology; D013997:Time Factors
C412896:2-(4-morpholinyl)ethyl butyrate; D002087:Butyrates; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009025:Morpholines; D006655:Histone Deacetylases