ABSTRACT
The concept of a "topographical memory" in lymphocytes implies a stable expression of homing receptors mediating trafficking of lymphocytes back to the tissue of initial activation. However, a significant plasticity of the gut-homing receptor α4ß7 was found in CD8+ T cells, questioning the concept. We now demonstrate that α4ß7 expression in murine CD4+ memory T cells is, in contrast, imprinted and remains stable in the absence of the inducing factor retinoic acid (RA) or other stimuli from mucosal environments. Repetitive rounds of RA treatment enhanced the stability of de novo induced α4ß7. A novel enhancer element in the murine Itga4 locus was identified that showed, correlating to stability, selective DNA demethylation in mucosa-seeking memory cells and methylation-dependent transcriptional activity in a reporter gene assay. This implies that epigenetic mechanisms contribute to the stabilization of α4ß7 expression. Analogous DNA methylation patterns could be observed in the human ITGA4 locus, suggesting that its epigenetic regulation is conserved between mice and men. These data prove that mucosa-specific homing mediated by α4ß7 is imprinted in CD4+ memory T cells, reinstating the validity of the concept of "topographical memory" for mucosal tissues, and imply a critical role of epigenetic mechanisms.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Integrin alpha4/metabolism , Intestines/immunology , Receptors, Lymphocyte Homing/metabolism , T-Lymphocyte Subsets/immunology , Animals , Cell Movement , Cells, Cultured , DNA Methylation , Enhancer Elements, Genetic/genetics , Epigenesis, Genetic , Gene Expression Regulation , Immunologic Memory , Integrin alpha4/genetics , Integrin beta Chains/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Tretinoin/metabolismABSTRACT
Regulatory T cells (Treg) harbor great therapeutic potential for the treatment of autoimmune diseases due to their potent suppressive capacity. The majority of these cells express the transcription factor Foxp3, which is critical for both development and function of Treg. We discuss here our recent data indicating a contribution of epigenetic regulation for the permanent expression of Foxp3 in stable Treg a finding that is of significant importance if Treg are devised for clinical applications.
