Junghee J Shin1, Jason Catanzaro2, Jennifer R Yonkof3, Ottavia Delmonte4, Keith Sacco4, Min Sun Shin1, Srikar Reddy1, Paula J Whittington1,5, Gary Soffer2, Peter J Mustillo3, Kathleen E Sullivan6,7, Luigi D Notarangelo4, Roshini S Abraham3,8, Neil Romberg6,7, Insoo Kang9. 1. Section of Rheumatology, Allergy and Immunology, Departments of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA. 2. Section of Pulmonology, Allergy, Immunology and Sleep Medicine, Department of Pediatrics, Yale University School of Medicine, New Haven, CT, 06520, USA. 3. Division of Allergy and Immunology, Nationwide Children's Hospital, Columbus, OH, 43212, USA. 4. Laboratory of Clinical Immunology and Microbiology, National Institution of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20893, USA. 5. Department of Allergy and Immunology, Mid-Atlantic Permanente Medical Group of Kaiser Permanente, Rockville, MD, 20852, USA. 6. Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. 7. Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA. 8. Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, 43212, USA. 9. Section of Rheumatology, Allergy and Immunology, Departments of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA. Insoo.kang@yale.edu.
Abstract
PURPOSE: CD40 ligand (CD40L)-deficient patients display increased susceptibilities to infections that can be mitigated with effective prophylactic strategies including immunoglobulin G (IgG) replacement and prophylactic antibiotics. CD8+ T-cell senescence has been described in CD40L deficiency, but it is unclear if this is an intrinsic feature of the disease or secondary to infectious exposures. To address this question, we assessed CD8+ T-cell senescence and its relationship to clinical histories, including prophylaxis adherence and infections, in CD40L-deficient patients. METHODS: Peripheral CD8+ T-cells from seven CD40L-deficient patients and healthy controls (HCs) were assessed for senescent features using T-cell receptor excision circle (TREC) analysis, flow cytometry, cytometry by time of flight (CyTOF) and in vitro functional determinations including CMV-specific proliferation and cytokine release assays. RESULTS: Three patients (5, 28, and 34 years old) who were poorly adherent to immunoglobulin G replacement and Pneumocystis jirovecii pneumonia (PJP) prophylaxis and/or experienced multiple childhood pneumonias (patient group 1) had an expansion of effector memory CD8+ T-cells with the senescent phenotype when compared to HCs. Such changes were not observed in the patient group 2 (four patients, 16, 22, 24, and 33 years old) who were life-long adherents to prophylaxis and experienced few infectious complications. CyTOF analysis of CD8+ T-cells from the 5-year-old patient and older adult HCs showed similar expression patterns of senescence-associated molecules. CONCLUSIONS: Our findings support that recurrent infections and non-adherence to prophylaxis promote early CD8+ T-cell senescence in CD40L deficiency. Premature senescence may increase malignant susceptibilities and further exacerbate infectious risk in CD40L-deficient patients.
PURPOSE: CD40 ligand (CD40L)-deficient patients display increased susceptibilities to infections that can be mitigated with effective prophylactic strategies including immunoglobulin G (IgG) replacement and prophylactic antibiotics. CD8+ T-cell senescence has been described in CD40L deficiency, but it is unclear if this is an intrinsic feature of the disease or secondary to infectious exposures. To address this question, we assessed CD8+ T-cell senescence and its relationship to clinical histories, including prophylaxis adherence and infections, in CD40L-deficient patients. METHODS: Peripheral CD8+ T-cells from seven CD40L-deficient patients and healthy controls (HCs) were assessed for senescent features using T-cell receptor excision circle (TREC) analysis, flow cytometry, cytometry by time of flight (CyTOF) and in vitro functional determinations including CMV-specific proliferation and cytokine release assays. RESULTS: Three patients (5, 28, and 34 years old) who were poorly adherent to immunoglobulin G replacement and Pneumocystis jirovecii pneumonia (PJP) prophylaxis and/or experienced multiple childhood pneumonias (patient group 1) had an expansion of effector memory CD8+ T-cells with the senescent phenotype when compared to HCs. Such changes were not observed in the patient group 2 (four patients, 16, 22, 24, and 33 years old) who were life-long adherents to prophylaxis and experienced few infectious complications. CyTOF analysis of CD8+ T-cells from the 5-year-old patient and older adult HCs showed similar expression patterns of senescence-associated molecules. CONCLUSIONS: Our findings support that recurrent infections and non-adherence to prophylaxis promote early CD8+ T-cell senescence in CD40L deficiency. Premature senescence may increase malignant susceptibilities and further exacerbate infectious risk in CD40L-deficient patients.
Authors: Emily S J Edwards; Julia Bier; Theresa S Cole; Melanie Wong; Peter Hsu; Lucinda J Berglund; Kaan Boztug; Anthony Lau; Emma Gostick; David A Price; Michael O'Sullivan; Isabelle Meyts; Sharon Choo; Paul Gray; Steven M Holland; Elissa K Deenick; Gulbu Uzel; Stuart G Tangye Journal: J Allergy Clin Immunol Date: 2018-05-22 Impact factor: 10.793
Authors: M Teresa de la Morena; David Leonard; Troy R Torgerson; Otavio Cabral-Marques; Mary Slatter; Asghar Aghamohammadi; Sharat Chandra; Luis Murguia-Favela; Francisco A Bonilla; Maria Kanariou; Rongras Damrongwatanasuk; Caroline Y Kuo; Christopher C Dvorak; Isabelle Meyts; Karin Chen; Lisa Kobrynski; Neena Kapoor; Darko Richter; Daniela DiGiovanni; Fatima Dhalla; Evangelia Farmaki; Carsten Speckmann; Teresa Español; Anna Shcherbina; Imelda Celine Hanson; Jiri Litzman; John M Routes; Melanie Wong; Ramsay Fuleihan; Suranjith L Seneviratne; Trudy N Small; Ales Janda; Liliana Bezrodnik; Reinhard Seger; Andrea Gomez Raccio; J David M Edgar; Janet Chou; Jordan K Abbott; Joris van Montfrans; Luis Ignacio González-Granado; Nancy Bunin; Necil Kutukculer; Paul Gray; Gisela Seminario; Srdjan Pasic; Victor Aquino; Christian Wysocki; Hassan Abolhassani; Morna Dorsey; Charlotte Cunningham-Rundles; Alan P Knutsen; John Sleasman; Beatriz Tavares Costa Carvalho; Antonio Condino-Neto; Eyal Grunebaum; Helen Chapel; Hans D Ochs; Alexandra Filipovich; Mort Cowan; Andrew Gennery; Andrew Cant; Luigi D Notarangelo; Chaim M Roifman Journal: J Allergy Clin Immunol Date: 2016-09-30 Impact factor: 10.793
Authors: Raquel Ruiz-García; Carmen Rodríguez-Vigil; Francisco Manuel Marco; Fernando Gallego-Bustos; María José Castro-Panete; Laura Diez-Alonso; Carlos Muñoz-Ruiz; Jesús Ruiz-Contreras; Estela Paz-Artal; Luis Ignacio González-Granado; Luis Miguel Allende Journal: Front Immunol Date: 2017-07-12 Impact factor: 7.561
Authors: Dominic Paquin-Proulx; Bianca A N Santos; Karina I Carvalho; Myrthes Toledo-Barros; Ana Karolina Barreto de Oliveira; Cristina M Kokron; Jorge Kalil; Markus Moll; Esper G Kallas; Johan K Sandberg Journal: PLoS One Date: 2013-10-09 Impact factor: 3.240