Impact of diet-induced dyslipidemia on skin inflammation driven by autoreactive lipid-specific t cells

The National Institute of Allergy and Infectious Diseases awarded Northwestern University $240,000 on June 2, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate the mechanisms linking diet-induced dyslipidemia to skin inflammation driven by autoreactive lipid-specific T cells in psoriasis.

The research uses a double transgenic mouse model expressing human group 1 CD1 molecules and a CD1B-restricted T cell receptor specific for self-phospholipids, crossed onto an LDL receptor-deficient background and fed a high-fat diet to induce psoriasiform skin inflammation. The study aims to define the transcriptional, cytokine, and metabolic programs of CD1B-autoreactive T cells through single-cell RNA sequencing, flow cytometry, and metabolic profiling, and to characterize their interactions with other immune cells under dyslipidemic conditions. The work is grounded in translational relevance: CD1B expression is elevated in psoriatic skin, and circulating CD1B-autoreactive T cell frequency is increased in psoriasis patients, suggesting that diet-induced hyperlipidemia chronically activates self-lipid-specific T cells and drives IL-17-biased inflammation.

The award supports work performed in Chicago, Illinois, with a period of performance from June 2, 2026, through May 31, 2028. This is a Project Grant, a form of assistance funding supporting research by a named principal investigator.

Abstract

Psoriasis is a chronic inflammatory skin disease frequently associated with dyslipidemia, characterized by elevated levels of LDL, cholesterol, and triglycerides. While lipid metabolism is implicated in psoriasis pathogenesis, the mechanisms linking dyslipidemia to immune dysregulation remain poorly defined. Recent studies suggests that t cells recognizing self-lipid antigens presented by group 1 CD1 molecules (CD1A, CD1B, CD1C) may act as immunologic sensors of lipid dysregulation, contributing to skin inflammation. However, due to the lack of group 1 CD1 molecules in mice, mechanistic studies of these t cells in vivo have been limited. To address this GAP, we developed a double transgenic mouse model expressing human group 1 CD1 molecules (HCD1TG) and a CD1B-restricted TCR specific for self-phospholipids (HJ1TG). Crossing these mice onto LDL receptor-deficient (ldlr-/-) background and feeding them a high-FAT diet (HFD) induces spontaneous psoriasiform skin inflammation characterized by dermal neutrophil infiltration, keratinocyte hyperplasia, and a TH17-skewed CD1B-autoreactive t cell response. Supporting translational relevance of this model, CD1B expression is elevated in psoriatic skin, and the frequency of circulating CD1B-autoreactive t cells is increased in psoriasis patients. We hypothesize that diet-induced hyperlipidemia chronically activates self-lipid-specific CD1B-restricted t cells and drives IL-17-biased inflammation in the skin. To test this, we propose the following aims: aim 1: investigate the mechanisms by which dyslipidemia promotes skin inflammation through CD1B- autoreactive t cells. We will use single-cell RNA sequencing, flow cytometry, and metabolic profiling to define the transcriptional, cytokine, and metabolic programs of CD1B-autoreactive t cells and their interactions with other immune cells under dyslipidemic conditions induced by HFD. Aim 2: determine the reversibility of dyslipidemia-induced skin inflammation and t cell activation following dietary normalization. Using a diet-switch model, we will examine skin pathology, t cell function, lipid profiles, and gene expression changes in mice transitioned from HFD to normal chow. Aim 3: evaluate the contribution of GUT microbiota to HFD-induced immune dysregulation and skin inflammation. We will utilize antibiotic treatment and metagenomic sequencing to investigate how microbial composition impacts systemic immune activation and CD1B-restricted t cell responses under dyslipidemic conditions. This study aims to define how lipid dysregulation influences autoreactive CD1B-restricted t cell responses, advancing understanding of the immunometabolic mechanisms in psoriasis and related inflammatory diseases. These findings may provide a foundation for targeting lipid-specific t cells as therapeutic interventions for dyslipidemia-associated skin inflammation.