GZMK+CD8+ T cells Target A Specific Acinar Cell Type in Sjögren's Disease

Thomas J F Pranzatelli; Paola Perez; Anson Ku; Bruno Matuck; Khoa Huynh; Shunsuke Sakai; Mehdi Abed; Shyh-Ing Jang; Eiko Yamada; Kalie Dominick; Zara Ahmed; Amanda Oliver; Rachael Wasikowski; Quinn T Easter; Alan N Baer; Eileen Pelayo; Zohreh Khavandgar; David E Kleiner; M Teresa Magone; Sarthak Gupta; Christopher Lessard; A Darise Farris; Peter D Burbelo; Daniel Martin; Robert J Morell; Changyu Zheng; Nicholas Rachmaninoff; Jose Maldonado-Ortiz; Xufeng Qu; Marit Aure; Mohammad H Dezfulian; Ross Lake; Sarah Teichmann; Daniel L Barber; Lam C Tsoi; Adam G Sowalsky; Katarzyna M Tyc; Jinze Liu; Johann Gudjonsson; Kevin M Byrd; Philip L F Johnson; John A Chiorini; Blake M Warner

doi:10.21203/rs.3.rs-3601404/v1

GZMK+CD8+ T cells Target A Specific Acinar Cell Type in Sjögren's Disease

Res Sq [Preprint]. 2024 Jul 11:rs.3.rs-3601404. doi: 10.21203/rs.3.rs-3601404/v1.

Authors

Thomas J F Pranzatelli^{1

2}, Paola Perez³, Anson Ku⁴, Bruno Matuck⁵, Khoa Huynh⁶, Shunsuke Sakai⁷, Mehdi Abed³, Shyh-Ing Jang³, Eiko Yamada³, Kalie Dominick³, Zara Ahmed³, Amanda Oliver⁸, Rachael Wasikowski⁹, Quinn T Easter⁵, Alan N Baer¹⁰, Eileen Pelayo¹⁰, Zohreh Khavandgar^{3

10}, David E Kleiner¹¹, M Teresa Magone¹², Sarthak Gupta^{3

13}, Christopher Lessard¹⁴, A Darise Farris¹⁵, Peter D Burbelo¹, Daniel Martin¹⁶, Robert J Morell¹⁶, Changyu Zheng¹⁶, Nicholas Rachmaninoff², Jose Maldonado-Ortiz^{1

3

10}, Xufeng Qu¹⁷, Marit Aure¹⁸, Mohammad H Dezfulian¹⁹, Ross Lake²⁰, Sarah Teichmann⁸, Daniel L Barber⁷, Lam C Tsoi⁹, Adam G Sowalsky⁴, Katarzyna M Tyc⁶, Jinze Liu⁶, Johann Gudjonsson⁹, Kevin M Byrd^{3

5}, Philip L F Johnson², John A Chiorini¹, Blake M Warner^{3

10}

Affiliations

¹ Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
² Department of Biology, University of Maryland College Park, MD, USA.
³ Salivary Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
⁴ Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Bethesda, MD, USA.
⁵ Lab of Oral & Craniofacial Innovation (LOCI), Department of Innovation & Technology Research, ADA Science & Research Institute, Gaithersburg, MD, USA.
⁶ Department of Biostatistics, Virginia Commonwealth University, VA, USA.
⁷ T-lymphocyte Biology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁸ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
⁹ Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.
¹⁰ Sjögren's Clinical Investigations Team, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
¹¹ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD, USA.
¹² Consult Services Section, National Eye Institute, National Institutes of Health, Bethesda MD, USA.
¹³ Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin, Diseases, National Institutes of Health, Bethesda MD, USA.
¹⁴ Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
¹⁵ Arthritis & Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
¹⁶ Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA.
¹⁷ Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
¹⁸ Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
¹⁹ Department of Genetics, Harvard Medical School, Boston, MA, USA.
²⁰ Laboratory of Genitourinary Cancer Pathogenesis (LCGP) Microscopy Core Facility, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Bethesda, MD, USA.

Abstract

Sjögren's Disease (SjD) is a systemic autoimmune disease without a clear etiology or effective therapy. Utilizing unbiased single-cell and spatial transcriptomics to analyze human minor salivary glands in health and disease we developed a comprehensive understanding of the cellular landscape of healthy salivary glands and how that landscape changes in SjD patients. We identified novel seromucous acinar cell types and identified a population of PRR4+CST3+WFDC2- seromucous acinar cells that are particularly targeted in SjD. Notably, GZMK+CD8 T cells, enriched in SjD, exhibited a cytotoxic phenotype and were physically associated with immune-engaged epithelial cells in disease. These findings shed light on the immune response's impact on transitioning acinar cells with high levels of secretion and explain the loss of this specific cell population in SjD. This study explores the complex interplay of varied cell types in the salivary glands and their role in the pathology of Sjögren's Disease.

Publication types

Preprint

Abstract

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