Title

Aberrant T-cell exhaustion in SCID survivors with poor T-cell reconstitution post transplant

Authors

Roxane Labrosse, Pediatric Immunology and Rheumatology Division, Department of Pediatrics, University of Montreal, QC, Canada.
Ines Boufaied, Cytokines and Adaptive Immunity Laboratory, Sainte-Justine University Hospital and Research Center, Montreal, QC, Canada.
Benoîte Bourdin, Cytokines and Adaptive Immunity Laboratory, Sainte-Justine University Hospital and Research Center, Montreal, QC, Canada.
Saideep Gona, Genetics, Genomics, and Systems Biology, Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, IL.
Haley E. Randolph, Genetics, Genomics, and Systems Biology, Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, IL.
Brent R. Logan, Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI.
Sara Bourbonnais, Cytokines and Adaptive Immunity Laboratory, Sainte-Justine University Hospital and Research Center, Montreal, QC, Canada.
Chloé Berthe, Cytokines and Adaptive Immunity Laboratory, Sainte-Justine University Hospital and Research Center, Montreal, QC, Canada.
Wendy Chan, Division of Allergy, Immunology and Blood and Marrow Transplantation, Department of Pediatrics, University of California San Francisco and UCSF Benioff Children's Hospital, San Francisco, CA.
Rebecca H. Buckley, Duke University Medical Center, Durham, NC.
Roberta E. Parrott, Duke University Medical Center, Durham, NC.
Geoffrey D. Cuvelier, Manitoba Blood and Marrow Transplant Program, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada.
Neena Kapoor, Blood and Marrow Transplant Program, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Sharat Chandra, Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
Blachy J. Dávila Saldaña, Division of Blood and Marrow Transplantation, Children's National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC.
Hesham Eissa, Children's Hospital of Colorado, University of Colorado School of Medicine, Aurora, CO.
Fred D. Goldman, Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL.
Jennifer Heimall, Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, PA.
Richard O'Reilly, Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY.
Sonali Chaudhury, Division of Hematology, Oncology, and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL.
Edward A. Kolb, Nemours Children's Health, Center for Cancer and Blood Disorders, Wilmington, DE.
Shalini Shenoy S, Division of Pediatric Hematology/Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.
Linda M. Griffith, Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
Michael Pulsipher, Blood and Marrow Transplant Program, Division of Hematology, Oncology and Blood and Marrow Transplantation, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Donald B. Kohn, Pediatrics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA.
Luigi D. Notarangelo, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
Sung-Yun Pai, Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Morton J. Cowan, Division of Allergy, Immunology and Blood and Marrow Transplantation, Department of Pediatrics, University of California San Francisco and UCSF Benioff Children's Hospital, San Francisco, CA.
Christopher C. Dvorak, Division of Allergy, Immunology and Blood and Marrow Transplantation, Department of Pediatrics, University of California San Francisco and UCSF Benioff Children's Hospital, San Francisco, CA.
Élie Haddad, Pediatric Immunology and Rheumatology Division, Department of Pediatrics, University of Montreal, QC, Canada.
Jennifer M. Puck, Division of Allergy, Immunology and Blood and Marrow Transplantation, Department of Pediatrics, University of California San Francisco and UCSF Benioff Children's Hospital, San Francisco, CA.
Luis B. Barreiro, Genetics, Genomics, and Systems Biology, Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, IL.

Document Type

Journal Article

Publication Date

8-17-2022

Journal

The Journal of allergy and clinical immunology

DOI

10.1016/j.jaci.2022.08.004

Keywords

(HCT); (SCID); T-cell exhaustion; conditioning chemotherapy; hematopoietic cell transplantation; immune reconstitution; severe combined immunodeficiency

Abstract

BACKGROUND: Severe combined immunodeficiency (SCID) comprises rare inherited disorders of immunity that require definitive treatment through hematopoietic cell transplantation (HCT) or gene therapy for survival. Despite successes of allogeneic HCT, many SCID patients experience incomplete immune reconstitution, persistent T-cell lymphopenia, and poor long-term outcomes. OBJECTIVE: We hypothesized that CD4+ T-cell lymphopenia could be associated with a state of T-cell exhaustion in previously transplanted SCID patients. METHODS: We analyzed markers of exhaustion in blood samples from 61 SCID patients at a median of 10.4 years post-HCT. RESULTS: Compared to post-HCT SCID patients with normal CD4+ T-cell counts, those with poor T-cell reconstitution showed lower frequency of naïve CD45RA+/CCR7+ T cells, recent thymic emigrants (RTEs), and T-cell receptor excision circles (TRECs). They also had a restricted TCR repertoire, increased expression of inhibitory receptors (PD1, 2B4, CD160, BTLA, CTLA-4), and increased activation markers (HLA-DR, perforin) on their total and naïve CD8+ T cells, suggesting T-cell exhaustion and aberrant activation, respectively. The exhaustion score of CD8+ T cells was inversely correlated with CD4+ T-cell count, RTEs, TRECs, and TCR diversity. Exhaustion scores were higher among recipients of unconditioned HCT, especially when further in time from HCT. Patients with fewer CD4+ T cells showed a transcriptional signature of exhaustion. CONCLUSION: Recipients of unconditioned HCT for SCID may develop late post-HCT T-cell exhaustion due to diminished production of T-lineage cells. Elevated expression of inhibitory receptors on their T cells may be a biomarker of poor long-term T-cell reconstitution. CLINICAL IMPLICATIONS: Hematopoietic cell transplantation for severe combined immunodeficiency may require conditioning to guarantee durable production of new T cells, preventing development of CD4+ T-cell lymphopenia and CD8+ T-cell exhaustion.

Department

Pediatrics

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