Barski Lab
Epigenomics of T cell Memory

Epigenomics of T cell Memory

The goal of this project is to understand the role of chromatin and gene poising in T helper (Th) cell differentiation and memory T cell function. Upon initial antigen stimulation, naïve T cells may differentiate into several lineages of effector T cells. The heterogeneity within the CD4+ effector/memory T cell compartment is critical for our ability to deal with diverse pathogens. For example, dedicated populations of CD4+ Th cells are required for promoting immune defense against intracellular infections (Th1 cells), helminth infections (Th2 cells) and fungal infections (Th17 cells). However, each of these differentiated states is also associated with human disease: Th1 and Th17 cells can promote autoimmunity, whereas Th2 cells can promote allergy and asthma. Thus, understanding and learning to exploit the mechanisms that underlie lineage choice and lineage maintenance is vital for understanding and treatment of immunological and infectious diseases. We are interested in epigenetic regulation of T cell lineage commitment and T cell memory.

Epigenomics of T cell Memory image.

Even though T cell receptor (TCR) stimulation coupled with co-stimulation is sufficient for the activation of both naïve and memory T cells, the memory cells are capable of producing lineage-specific cytokines much more rapidly than the naïve cells. The mechanisms behind this rapid recall response of the memory cells are still not completely understood. We have performed epigenetic profiling of human resting naïve, central and effector memory T cells using ChIP-Seq and found that unlike the naïve cells, the regulatory elements of the cytokine genes in the memory T cells are marked by activating histone modifications even in the resting state. Therefore, the ability to induce expression of rapid recall genes upon activation is associated with the deposition of positive histone modifications during memory T cell differentiation. We are now aiming to prove the causal relationship between the presence of epigenetic marks and cytokine gene reproducibility. If successful, this project will allow for epigenetic reprogramming of T cell responses. 

Chromatin Marks at the Th2 Cytokine Locus.

Chromatin Marks at the Th2 Cytokine Locus. (a) Human naïve and effector memory T (TEM) cells were isolated from blood and activated with anti-CD3/28 beads for 40 min, 150 min or 15 h. Expression of the cytokine genes, IL13 (a) and IL4 (c) was measured by RNA-Seq. ChIP-Seq profiles for active chromatin marks (H3K4me1, H3K4me3 and H2A.Z) are shown in resting cells (b). Putative regulatory elements are denoted on top. Gray boxes highlight the areas where epigenetic changes are observed. 

In a healthy organism, anergy is used as a mechanism to control self-reacting T cells. Although most such cells are eliminated by negative selection in the thymus, those that escape must be controlled by induction of clonal anergy or peripheral tolerance. Failure of peripheral tolerance is considered one of mechanisms leading to autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis.

Mechanistically, T-cell anergy results when  -cells receive a TCR signal that is not accompanied by a co-stimulatory signal (e.g. CD28). Anergic cells fail to produce cytokines or to proliferate upon repeated stimulation. Transcriptional pathways leading to anergy have been studied by several groups, and key transcription factors involved in the process have been identified, including NFAT, AP-1 and Egr3. It was also found that chromatin structure in anergic T cells differs from that in properly activated T cells at key loci, including the Il2 gene. We want to study the epigenomic structure in anergic T cells and compare it to that in normally activated T cells in order to better understand mechanisms underlying T-cell anergy.

Epigenetic Regulation of T-cell Anergy/Tolerance

Rapid Recall Ability of Memory T cells Encoded in their Epigenome

Rapid Recall Ability of Memory T cells is Encoded in their Epigenome.

From our published data, we propose a model of T cell memory in which the immunological memory state is encoded epigenetically through poising and transcriptional memory

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NIH Director’s New Innovator Award image.

NIH Director’s New Innovator Award: Direct Epigenetic Reprogramming of T Cells (DP2-GM-119134).

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