Histone deacetylase inhibitor uses p21(Cip1) to maintain anergy in CD4+ T cells

T cell anergy defined as antigen-specific proliferative unresponsiveness was induced in CD4+ T cells exposed to antigen (Ag) in the presence of the histone deacetylase (HDAC) inhibitors n-butyrate, trichostatin A or scriptaid. However, the ability of HDAC inhibitors to induce anergy in Th1 cells was not due to general histone hyperacetylation. Instead, the anergy induced by HDAC inhibitors was associated with upregulation of p21(Cip1), a secondary effect of histone acetylation. Induction of p21(Cip1) in the absence of histone hyperacetylation by exposure to okadaic acid also resulted in T cell anergy. In addition, Ag-specific p21(Cip1)-deficient CD4+ T cells were much less susceptible to anergy induction by n-butyrate. Thus, p21(Cip1) appears to mediate the proliferative unresponsiveness found in CD4+ T cell anergized by exposure to Ag in the presence of HDAC inhibitors.