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2555 Primary Immune Regulatory Disorders (PIRDs) That Amplify mTOR Signaling Share a T Cell Exhaustion-like Process

Program: Oral and Poster Abstracts
Session: 203. Lymphocytes and Acquired or Congenital Immunodeficiency Disorders: Poster II
Hematology Disease Topics & Pathways:
Research, Fundamental Science, autoimmune disorders, Translational Research, Diseases, Immune Disorders, immunodeficiency
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Peyton E Conrey1*, Jose Campos1*, Andrea Mauracher, MD PhD1*, Samir Sayed1*, Jolan E. Walter, MD, PhD2*, Helen Su, MD PhD3*, Sara Barmettler, MD4*, Jennifer W Leiding, MD5*, Megan Cooper, MD PhD6*, Suzanne P MacFarland, MD7*, Melanie A Ruffner, MD PhD1*, Jocelyn R Farmer, MD PhD8*, V. Koneti Rao, MD9 and Sarah E Henrickson, MD PhD1*

1Department of Pediatrics, Allergy Immunology Division, Children's Hospital of Philadelphia, Philadelphia, PA
2Division of Allergy & Immunology, Department of Pediatrics, Morsani College of Medicine, University of South Florida at Johns Hopkins All Children’s Hospital, St. Petersburg, FL
3NIAID, NIH, Bethesda, MD
4Massachusetts General Hospital, Boston, MA
5Johns Hopkins University School of Medicine, Baltimore, MD
6Department of Pediatrics, Washington University, St. Louis
7Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA
8Lahey Health, Boston, MA
9NIAID National Institutes of Health, Bethesda, MD

Background: Primary Immune Regulatory Disorders (PIRDs) are a complex and challenging-to-treat subset of Inborn Errors of Immunity (IEI), which are characterized by immune dysregulation leading to recurrent infections, lymphoproliferation, and autoimmunity including refractory cytopenias. Since many ultra-rare monogenic PIRDs exist, it is not feasible to design targeted therapies for each. An alternate strategy is to identify shared aspects of T cell dysfunction and strategies targeting them. We have focused our studies on PIRDs that chronically amplify T cell receptor (TCR) signaling, mimicking chronic infection. Under conditions of chronic inflammation and antigen presentation, seen during chronic infections, CD8 T cell exhaustion (Tex) can result and is characterized by increased inhibitory receptor expression, altered transcriptional networks, epigenetic poise, and impaired T cell functions including cytokine production. Here, we have evaluated CD8 T cell dysfunction in PIRDs, including the potential for Tex.

Methods: Deep immune phenotyping and T cell functional analyses were performed using CyTOF and spectral flow cytometry, in addition to single cell RNA-sequencing and CITE-seq from untreated PIRD and healthy control PBMCs. Finally, CRISPR/Cas9 editing in healthy control CD8 T cells was used to create a cellular disease model.

Results: We identified a Tex-like process in activated PI3 kinase delta syndrome (APDS), CTLA-4 haploinsufficiency, and Ras-associated Autoimmune Leukoproliferative Disease (RALD), which share increased mTOR activation. We identified increased PD-1, CD39, TIGIT and TOX expression on CD8 T cells consistent with a Tex-like phenotype. We also found impaired CD8 T cell cytokine and proliferation consistent with Tex. Lastly, a cellular model of CTLA-4 haploinsufficiency was created for perturbation studies to evaluate best available therapies and target novel therapeutics in these rare disorders.

Conclusion: By identifying shared patterns of CD8 T cell dysfunction in these ultra-rare disorders, we may both identify novel therapeutic strategies and increase our understanding of CD8 T cell function, including cytokine production.

Disclosures: Conrey: Intregal Molecular: Current Employment. Walter: Pharming: Consultancy, Speakers Bureau; Regeneron: Consultancy, Research Funding; Enzyvant: Consultancy; ADMA Biologicals: Consultancy, Research Funding; Grifols: Consultancy; CSL-Behring: Consultancy; X4 Pharmaceuticals Inc.: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Janssen: Research Funding; Chiesi: Research Funding; MustangBio: Research Funding; Octapharma: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding. Leiding: bluebird bio: Current Employment. Henrickson: Horizon Therapeutics: Consultancy.

*signifies non-member of ASH