The Interplay Between Epigenetic Regulation and CD8+ T Cell Differentiation/Exhaustion for T Cell Immunotherapy

Effective immunotherapy treats cancers by eradicating tumourigenic cells by activated tumour antigen-specific and bystander CD8+ T-cells. However, T-cells can gradually lose cytotoxicity in the tumour microenvironment, known as exhaustion. Recently, DNA methylation, histone modification, and chromatin architecture have provided novel insights into epigenetic regulations of T-cell differentiation/exhaustion, thereby controlling the translational potential of the T-cells. Thus, developing strategies to govern epigenetic switches of T-cells dynamically is critical to maintaining the effector function of antigen-specific T-cells. In this mini-review, we 1) describe the correlation between epigenetic states and T cell phenotypes; 2) discuss the enzymatic factors and intracellular/extracellular microRNA imprinting T-cell epigenomes that drive T-cell exhaustion; 3) highlight recent advances in epigenetic interventions to rescue CD8+ T-cell functions from exhaustion. Finally, we express our perspective that regulating the interplay between epigenetic changes and transcriptional programs provides translational implications of current immunotherapy for cancer treatments.

PP2A and Its Inhibitors in Helper T-Cell Differentiation and Autoimmunity

Protein phosphatase 2A (PP2A) is a highly complex heterotrimeric Ser/Thr phosphatase that regulates many cellular processes. The role of PP2A as a tumor suppressor has been extensively studied and reviewed. However, emerging evidence suggests PP2A constrains inflammatory responses and is important in autoimmune and neuroinflammatory diseases. Here, we reviewed the existing literature on the role of PP2A in T-cell differentiation and autoimmunity. We have also discussed the modulation of PP2A activity by endogenous inhibitors and its small-molecule activators as potential therapeutic approaches against autoimmunity.

Single-Cell Analysis Reveals the Immune Characteristics of Myeloid Cells and Memory T Cells in Recovered COVID-19 Patients With Different Severities

Despite many studies on the immune characteristics of Coronavirus disease 2019 (COVID-19) patients in the progression stage, a detailed understanding of pertinent immune cells in recovered patients is lacking. We performed single-cell RNA sequencing on samples from recovered COVID-19 patients and healthy controls. We created a comprehensive immune landscape with more than 260,000 peripheral blood mononuclear cells (PBMCs) from 41 samples by integrating our dataset with previously reported datasets, which included samples collected between 27 and 47 days after symptom onset. According to our large-scale single-cell analysis, recovered patients, who had severe symptoms (severe/critical recovered), still exhibited peripheral immune disorders 1–2 months after symptom onset. Specifically, in these severe/critical recovered patients, human leukocyte antigen (HLA) class II and antigen processing pathways were downregulated in both CD14 monocytes and dendritic cells compared to healthy controls, while the proportion of CD14 monocytes increased. These may lead to the downregulation of T-cell differentiation pathways in memory T cells. However, in the mild/moderate recovered patients, the proportion of plasmacytoid dendritic cells increased compared to healthy controls, accompanied by the upregulation of HLA-DRA and HLA-DRB1 in both CD14 monocytes and dendritic cells. In addition, T-cell differentiation regulation and memory T cell–related genes FOS, JUN, CD69, CXCR4, and CD83 were upregulated in the mild/moderate recovered patients. Further, the immunoglobulin heavy chain V3-21 (IGHV3-21) gene segment was preferred in B-cell immune repertoires in severe/critical recovered patients. Collectively, we provide a large-scale single-cell atlas of the peripheral immune response in recovered COVID-19 patients.

IFNγ and iNOS-Mediated Alterations in the Bone Marrow and Thymus and Its Impact on Mycobacterium avium-Induced Thymic Atrophy

Disseminated infection with the high virulence strain of Mycobacterium avium 25291 leads to progressive thymic atrophy. We previously showed that M. avium-induced thymic atrophy results from increased glucocorticoid levels that synergize with nitric oxide (NO) produced by interferon gamma (IFNγ) activated macrophages. Where and how these mediators act is not understood. We hypothesized that IFNγ and NO promote thymic atrophy through their effects on bone marrow (BM) T cell precursors and T cell differentiation in the thymus. We show that M. avium infection cause a reduction in the percentage and number of common lymphoid progenitors (CLP). Additionally, BM precursors from infected mice show an overall impaired ability to reconstitute thymi of RAGKO mice, in part due to IFNγ. Thymi from infected mice present an IFNγ and NO-driven inflammation. When transplanted under the kidney capsule of uninfected mice, thymi from infected mice are unable to sustain T cell differentiation. Finally, we observed increased thymocyte death via apoptosis after infection, independent of both IFNγ and iNOS; and a decrease on active caspase-3 positive thymocytes, which is not observed in the absence of iNOS expression. Together our data suggests that M. avium-induced thymic atrophy results from a combination of defects mediated by IFNγ and NO, including alterations in the BM T cell precursors, the thymic structure and the thymocyte differentiation.

New Insights into Epigenetic Regulation of T Cell Differentiation

Immature CD4− CD8− thymocytes progress through several developmental steps in the thymus, ultimately emerging as mature CD4+ (helper) or CD8+ (cytotoxic) T cells. Activation of naïve CD4+ and CD8+ T cells in the presence of specific cytokines results in the induction of transcriptional programs that result in their differentiation into effector or memory cells and in the case of CD4+ T cells, the adoption of distinct T-helper fates. Previous studies have shown that histone modification and DNA methylation play important roles in each of these events. More recently, the roles of specific epigenetic regulators in T cell differentiation have been clarified. The identification of the epigenetic modifications and modifiers that control mature T cell differentiation and specification has also provided further insights into how dysregulation of these processes can lead to cancer or autoimmune diseases. In this review, we summarize recent findings that have provided new insights into epigenetic regulation of T cell differentiation in both mice and humans.