Transmethylation in immunity and autoimmunity

Abstract

The activation of immune cells is mediated by a network of signaling proteins that can undergo post-translational modifications critical for their activity. Methylation of nucleic acids or proteins can have major effects on gene expression as well as protein repertoire diversity and function. Emerging data indicate that indeed many immunologic functions, particularly those of T cells, including thymic education, differentiation and effector function are highly dependent on methylation events. The critical role of methylation in immunocyte biology is further documented by evidence that autoimmune phenomena may be curtailed by methylation inhibitors. Additionally, epigenetic alterations imprinted by methylation can also exert effects on normal and abnormal immune responses. Further work in defining methylation effects in the immune system is likely to lead to a more detailed understanding of the immune system and may point to the development of novel therapeutic approaches.

Conflict of interest statement

10. Conflict of interest statement

The author(s) declare that there are no conflicts of interest.

Copyright © 2011. Published by Elsevier Inc.

Figures

Figure 1

Biochemical pathway of protein and DNA transmethylation. Methyltransferases (MT) catalyze the transfer of methyl groups from SAM to either proteins or DNA, resulting in conversion of SAM to SAH. SAH is then hydrolyzed into adenosine and homo-cysteine by SAHase. If the balance between SAM and SAH concentrations favor SAH, SAH can then provide negative feedback inhibition of transmethylation activity allowing restoration of SAM concentrations. Thus, pharmacological blockade of SAHase increases intracellular levels of SAH, thereby indirectly blocking MT activity.

Figure 2

Arginine methylation. Monomethylarginine is generated upon transfer of a methyl group from SAM to the guanidino amino group of arginine. Type I protein arginine methyltransferases (PRMTs 1, 3, 4, 6 and 8) then transfer a second methyl group to the same nitrogen, resulting in an asymmetric dimethylarginine. Type II PRMTs (PRMTs 5 and 7) transfer the additional methyl group to the opposite terminal nitrogen, creating symmetric dimethylarginine. PRMT2 is not yet classified.

Figure 3

Methylation events during thymocyte development. Gene methylation status fluctuates during thymocyte differentiation. Double-negative (DN) thymocytes exhibit methylated TCR loci and expression of TCRβ is closely associated with signaling through the IL-7Rα and demethylation of the TCRβ locus, leading to locus accessibility and VDJ recombination. The first step (1) in thymocyte differentiation is the transition from DN to double-positive (DP) CD4+CD8+ cells and is accompanied by demethylation of CD8α and CD8β. The second (2) and third (3) steps lead to intermediate thymocyte subpopulations, e.g., CD4loCD8lo and CD4+CD8lo, and correspond to acquisition of a functionally rearranged TCR, again implying DNA and protein methylation modifications. Finally, CD4+ or CD8+ T cells are produced (4), but whether methylation status affects CD4 or CD8 expression remains to be clearly elucidated. However, retention of demethylated CD8 genes in CD4+ single cells was demonstrated, and de novo remethylation of CD8α genes was associated with apoptosis of misselected thymic CD8+ T cell emigrants that do not correctly recognize MHC class I in the periphery, inhibiting development of autoimmune disease. Interestingly, inhibition of SAHase activity by MDL28842 leads to arrested thymocyte differentiation at the CD8lo and CD4+CD8+ DP stages associated with decreased CD8 and CD4 mRNA. This effect may be a result of MDL28842 inhibition of PRMT4 and/or Vav1 activity, as both have been implicated in thymocyte developmental arrest.

Figure 4

Putative role of methylation during CD4+ T cell and global immune responses. DNA or histone methylation allows DNA structural changes and transcription factor accessibility. These events occur during CD4+ T cell differentiation and direct CD4+-mediated helper responses. Th1 and Th2 differentiationismediatedbymethylationofthe IL-4 gene and demethylationofthe IFN-γ gene,ormethylation of the IFN-γ gene and demethylation of the IL-4 gene, respectively. Moreover, histone modifications in the IL-17 and IL-17F promoter regions (e.g. H3K4 trimethylation and H3 acetylation) lead to the expression of these cytokines and a Th17 response. Thus, SAHase inhibition may block T helper responses by ineffective epigenetic events (DNA or protein) leading to defective humoral- and cell-mediated responses, [38,51,52]. H3K4, lysine 4 of histone 3; 3met, trimethylation; ac, acetylation; met, metylation).