Mechanistic insights into pathogenic CD8+ t cells… (F30AI200188) – Project Grant to The Washington University

Abstract: Although recent decades have seen great strides in precision medicine, the field of autoimmunity still lags behind. Current treatment strategies for autoimmune disease are based on broad immunosuppression, which is only effective in ~60% of patients and risks opportunistic infections. Precise targeting of the pathogenic component of the immune system to increase efficacy and limit toxicity is a major unmet need. Targeted approaches hold particular promise for the "HLA-B27 syndromes." this family of autoimmune diseases [including ankylosing spondylitis (as), acute anterior uveitis (AAU), reactive arthritis, psoriatic arthritis (PSA), and inflammatory bowel disease-related arthritis] is named for its strong association with the B27 allele of the human leukocyte antigen (HLA) super-locus. IT is hypothesized that the HLA-B27 allele promotes autoimmunity by activating pathogenic CD8+ t cells. These pathogenic CD8+ t cells are first activated by bacterial antigens in the GUT and subsequently react to structurally similar self-antigens in the joint, eye, and other peripheral tissues. Most pathogenic CD8 t cells use TRBV9 to produce their t cell receptors (tcrs), and their depletion with a TRBV9-depleting monoclonal antibody ameliorates disease in some patients. However, anti-TRBV9 therapy is not a broadly generalizable solution, as ~25% of pathogenic CD8 t cells can utilize a other trbv gene segments to generate their cross-reactive tcrs. A shared upstream cytokine or transcription factor specific to the pathogenic cells would be a more ideal therapeutic target. My preliminary analysis of the pathogenic cells' transcriptomic profiles suggests that they are transcriptionally distinct from conventional effector CD8+ t cells and that they are regulated by the cytokine tumor necrosis factor-like cytokine 1A (TL1A) and the transcription factor cebpd. I hypothesize that the pathogenic cells' activity is induced by these two factors. I will first activate the pathogenic cells in the presence or absence of TL1A to determine whether TL1A augments cell proliferation and cytokine production in vitro. I will also generate a TL1A-stimulated pathogenic CD8+ t cell gene signature with bulk RNA-SEQ and apply IT to single-cell and spatial data to test if pathogenic cells receive TL1A stimulation in vivo. For cebpd, i will predict the activity of cebpd in silico using machine learning approaches. I will then validate my findings in vitro by performing reciprocal forced expression and crispr knockout experiments to determine the effects of cebpd modulation on pathogenic cell cytokine output and proliferation. Lastly, i will perform paired scrnaseq + sctcrseq to investigate the effects of cebpd knockout on downstream transcriptional programming. I will pursue this training under the direction of a multidisciplinary advisory committee including physician-scientists, immunologists, and computational biologists. The blend of wet and dry lab techniques that i will learn for this proposal, along with its focus on identifying targets that can be taken from bench to bedside, will ultimately prepare me for a career as a physician-scientist leading a hybrid wet/dry translational immunology lab.

Action	Obligated	Date
Amendment	$37,312	May 22, 2026
Amendment	$37,312	May 22, 2026
Original award	$0	May 22, 2026

Mechanistic insights into pathogenic CD8+ t cells in HLA-B27+ autoimmunity

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