T Follicular Helper Cell-Dependent Clearance of a Persistent Virus Infection Requires T Cell Expression of the Histone Demethylase UTX

Abstract

Summary Epigenetic changes, including histone methylation, control T cell differentiation and memory formation, though the enzymes that mediate these processes are not clear. We show that UTX, a histone H3 lysine 27 (H3K27) demethylase, supports T follicular helper (Tfh) cell responses that are essential for B cell antibody generation and the resolution of chronic viral infections. Mice with a T cell-specific UTX deletion had fewer Tfh cells, reduced germinal center responses, lacked virus-specific IgG, and were unable to resolve chronic lymphocytic choriomeningitis virus infections. UTX-deficient T cells showed decreased expression of interleukin-6 receptor-α and other Tfh cell-related genes that were associated with increased H3K27 methylation. Additionally, Turner Syndrome subjects, who are predisposed to chronic ear infections, had reduced UTX expression in immune cells and decreased circulating CD4+ CXCR5+ T cell frequency. Thus, we identify a critical link between UTX in T cells and immunity to infection.

Histone Demethylase KDM6A Controls the Mammary Luminal Lineage through Enzyme-Independent Mechanisms

“…Of note, in these cases, the H3K27me3 demethylase activity of KDM6A appears to be required for its function. T follicular helper cells are particularly sensitive to the presence of KDM6A, which asserts its function through its enzymatic activity (55). Cardiac development is severely impaired in the absence of KDM6A and partially dependent on its enzymatic activity (5,6).…”

Pleiotropic Functions of H3K27Me3 Demethylases in Immune Cell Differentiation

“…Indeed, S1pr1 expression in mature thymocytes depends both on Utx demethylase activity [50] and on the adaptor Ptip1 [54], which is part with Utx of Ktm2c and Ktm2d complexes [72]. Such combinatorial impacts on H3K27Me3 removal and gene expression are likely to account for the pleiotropic effects of Jmjd3 disruption in Th1 effector T cell differentiation [81], or of Utx during follicular helper T cell differentiation [82] and hematopoiesis [83]. Delineating the respective impact of these multiple activities will be an important challenge for the field.…”

Regulators of Tfh Cell Differentiation

“…Robust regulation of Tfh cell response and subsequent antibody maturation are critical for infection clearance (2, 3), whereas aberrancy in controlling Tfh immune response is implicated in progression of autoimmune diseases such as systemic lupus erythematosus (SLE), arthritis, and type I/II diabetes (4–10). Moreover, Tfh cells were found to be choice of cells for HIV virus replication and survival (3, 11, 12). Because of association of Tfh cell with pathogenic as well as autoimmune diseases, attempts were made to increase or decrease Tfh cell number in order to reduce disease severity, pathology, and infection.…”