Aberrant T-cell exhaustion in severe combined immunodeficiency survivors with poor T-cell reconstitution after transplantation

• DOI: 10.1016/j.jaci.2022.08.004
• Publication Date: 2022-08-17T18:44:38Z
• Authors: Roxane Labrosse; Ines Boufaied; Benoîte Bourdin; Saideep Gona; Haley E. Randolph; Brent R. Logan; Sara Bourbonnais; Chloé Berthe; Wendy Chan; Rebecca H. Buckley; Roberta E. Parrott; Geoffrey D.E. Cuv...; Neena Kapoor; Sharat Chandra; Blachy J. Dávila ...; Hesham Eissa; Fred D. Goldman; Jennifer Heimall; Richard O’Reilly; Sonali Chaudhury; Edward A. Kolb; Shalini Shenoy; Linda M. Griffith; Michael Pulsipher; Donald B. Kohn; Luigi D. Notarangelo; Sung-Yun Pai; Morton J. Cowan; Christopher C. Dv...; Élie Haddad; Jennifer M. Puck; Luis B. Barreiro; Hélène Decaluwe
• Keywords: Conditioning chemotherapy; ICTS (Institute of Clinical and Translational Sciences); Hematopoietic Stem Cell Transplantation; Receptors, Antigen, T-Cell; 610; immune reconstitution; CD8-Positive T-Lymphocytes; hematopoietic cell transplantation (HCT); T-Cell; T-Cell Exhaustion; 3. Good health; T-cell exhaustion; Antigen; Lymphopenia; Receptors; Medicine and Health Sciences; Humans; severe combined immunodeficiency (SCID); Severe Combined Immunodeficiency

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.We hypothesized that CD4+ T-cell lymphopenia could be associated with a state of T-cell exhaustion in previously transplanted SCID patients.We analyzed markers of exhaustion in blood samples from 61 SCID patients at a median of 10.4 years after HCT.Compared to post-HCT SCID patients with normal CD4+ T-cell counts, those with poor T-cell reconstitution showed lower frequency of naive CD45RA+/CCR7+ T cells, recent thymic emigrants, and TCR excision circles. They also had a restricted TCR repertoire, increased expression of inhibitory receptors (PD-1, 2B4, CD160, BTLA, CTLA-4), and increased activation markers (HLA-DR, perforin) on their total and naive 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, recent thymic emigrants, TCR excision circles, 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.Recipients of unconditioned HCT for SCID may develop late post-HCT T-cell exhaustion as a result of 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.