The role of xist in t cell activation and female-biased autoimmunity

The National Institute of Allergy and Infectious Diseases awarded the University of California, Los Angeles $184,276 on November 16, 2025, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to support research investigating the role of XIST, a long non-coding RNA expressed exclusively in females, in T cell activation and female-biased autoimmunity.

The research addresses the observation that approximately 80 percent of autoimmune disease cases occur in females, despite incompletely understood mechanisms beyond sex hormones and chromosomal differences. XIST is more highly expressed in peripheral blood mononuclear cells from females with autoimmunity compared to healthy controls, suggesting a role in predisposing females to autoimmune disease. Preliminary studies using T cell-specific XIST knockout mice show that XIST-deficient CD4+ T cells exhibit defective proliferation and reduced proinflammatory cytokine production. The research will use ATAC-, RNA-, and RAP-sequencing in unstimulated and anti-CD3 stimulated XIST-deficient and wild-type CD4+ T cells to explore mechanisms by which XIST regulates T cell effector function and will evaluate the role of T cell-intrinsic XIST in autoimmune pathogenesis.

UCLA's Office of Research Administration serves as the recipient organization. Performance occurs in Los Angeles, California, with a period of performance extending through June 30, 2027.

Abstract

Approximately 80% of individuals affected by autoimmune disease are female. While divergent SEX hormones and chromosomes are known to contribute to SEX bias, the roles of additional SEX-specific factors are poorly understood. Xist, for instance, is a long non-coding RNA (lncrna) expressed exclusively in females. Notably, xist is more highly expressed in pbmcs from females with autoimmunity compared to healthy controls, suggesting a possible role for xist in predisposing females to autoimmunity. Xist is a key regulator of x-linked gene expression, facilitating x chromosome inactivation (XCI) during early embryonic development. Recent work has identified xist-mediated regulation of autosomal genes, a previously unappreciated xist function, in cell types with atypical, dispersed xist distribution. We and others have noted atypical, dispersed xist in activated CD4+ t cells, an immune cell type critical in autoimmune pathogenesis. To study xist in t cells and autoimmune pathogenesis, we engineered mice with t cell-specific xist knockout. Preliminary studies reveal xist-deficient CD4+ t cells are defective in proliferation and proinflammatory cytokine production, suggesting a critical role for xist in t cell activation. However, the (1) mechanism by which xist alters t cell effector function and (2) significance of xist-driven phenotypic changes for autoimmune pathogenesis are not known. This proposal will test the hypothesis that xist drives x-linked and autosomal chromatin accessibility and gene expression changes that support a proinflammatory t cell phenotype and contribute to female bias in autoimmunity. In aim 1, we will perform atac-, RNA-, and RAP-sequencing in unstimulated and anti-CD3 stimulated xist- deficient and WT CD4+ t cells to explore the mechanisms by which xist regulates t cell effector function. In aim 2, we will evaluate the role of t cell-intrinsic xist in autoimmune pathogenesis using a mouse model of the female-biased, t cell-driven autoimmune disease, sjogren's syndrome (SS). These studies will elucidate xist function in t cells and explore t cell-intrinsic xist as a potential determinant of female bias in autoimmunity. This work is guided by experts in t cell biology (maureen SU, MD - sponsor; GAY crooks, MD - thesis committee), lncrna biology (kathrin plath, PHD - cosponsor), bioinformatics (willy hugo, PHD - collaborator), and SEX differences in biology (karen reue, PHD - thesis committee) at the university of california LOS angeles. The trainee, nicole wilkinson, is richly supported for the work in this proposal and in reaching her career goal of running a translational immunology lab.