Epigenetics and the adaptive immune response

Abstract

Cells of the adaptive immune response undergo dynamic epigenetic changes as they develop and respond to immune challenge. Plasticity is a necessary prerequisite for the chromosomal dynamics of lineage specification, development, and the immune effector function of the mature cell types. The alterations in DNA methylation and histone modification that characterize activation may be integral to the generation of immunologic memory, thereby providing an advantage on secondary exposure to pathogens. While the immune system benefits from the dynamic nature of the epigenome, such benefit comes at a cost - increased likelihood of disease-causing mutation.

Figure 1. DNA methylation and DNA methyltransferases

A. The figure depicts enzymatic methylation at C5 of cytosine by DNA methyltransferases. 5-methylcytosine serves as a substrate for TET family enzymes which oxidize the methyl carbon to generate 5-hydroxymethyl cytosine. B. The mammalian DNMT family members are depicted in cartoon fashion. Domains are indicated where relevant.

Figure 2. Lysine modification as an epigenetic mark

The figure depicts lysine acetylation (top) and methylation (bottom). The epsilon amino group of lysine is acetylated by histone acetyltransferase enzymes (HATs). Acetyl-lysine is deacetylated by histone deacetylases (HDACs). Lysine can also be modified by the addition of one, two or three methyl groups. Methylation of lysine retains the positive charge, unlike acetylation which neutralizes it.

Figure 3. T cell development in the thymus and differentiation in the periphery

A. This figure depicts T cell development in the thymus. B. This figure depicts the various Th subtypes. The Th subtypes (top), the key cytokine responsible for initiating differentiation (middle), and the key transcription factors responsible for maintaining differentiation (bottom). C. This figure depicts T cell differentiation into effector, effector memory (Tem) and central memory (Tcm) cells.

Figure 4. V(D)J recombination

A. Schematic diagram of V(D)J recombination. A 12 (gray triangle) and 23 (blue triangle) RSS are bound by the same RAG1/2 complex (green square). Couple cleavage occurs to generate the two products of the reaction hairpin sealed coding ends (left) and blunt signal ends (right). The hairpins are opened by Artemis, repaired and ligated by the NHEJ pathway that creates a novel coding junction (yellow rectangle) between the two coding gene segments. The signal ends are repaired by the NHEJ pathway. B. Schematic of an inaccessible or accessible RSS. Inacessible RSS chromatin (top) has been correlated with DNA methylation (filled red circles), high nucleosome occupancy (gray ovals), H3K9me and a lack of transcription (crossed out arrow). Accessible RSS chromatin (bottom) has been correlated with loss of DNA methylation (open red circles), nucleosome loss or repositioning (green ovals), H3K4me3, H3 and H4 acetylation, and active transcription (arrow).

Figure 5. B cell development in the bone marrow and differentiation in the periphery

A. The figure depicts B cell development in the bone marrow. B. The figure depicts the various mature B cell populations found in the periphery. C. The figure depicts B cell maturation during a germinal center reaction.

Figure 6. Deamination of cytosine by AID

The proposed mechanism for enzymatic deamination of cytosine by AID/APOBEC enzymes involves production of an activated intermediate where the enzyme is covalently linked to the pyrimidine base through an oxygen atom. The intermediate is resolved by attack of a water molecule, regenerating the active enzyme and uracil. The reaction mechanism proceeds unaltered in the presence of a methyl carbon at the 5 position of the ring. However, the resulting product is thymidine, rather than uracil.