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Aberrant T-cell exhaustion in severe combined immunodeficiency survivors with poor T-cell reconstitution after transplantation. 2023
Roxane Labrosse, and
Ines Boufaied, and
Benoîte Bourdin, and
Saideep Gona, and
Haley E Randolph, and
Brent R Logan, and
Sara Bourbonnais, and
Chloé Berthe, and
Wendy Chan, and
Rebecca H Buckley, and
Roberta E Parrott, and
Geoffrey D E Cuvelier, and
Neena Kapoor, and
Sharat Chandra, and
Blachy J Dávila Saldaña, and
Hesham Eissa, and
Fred D Goldman, and
Jennifer Heimall, and
Richard O'Reilly, and
Sonali Chaudhury, and
Edward A Kolb, and
Shalini Shenoy, and
Linda M Griffith, and
Michael Pulsipher, and
Donald B Kohn, and
Luigi D Notarangelo, and
Sung-Yun Pai, and
Morton J Cowan, and
Christopher C Dvorak, and
Élie Haddad, and
Jennifer M Puck, and
Luis B Barreiro, and
Hélène Decaluwe
Pediatric Immunology and Rheumatology Division, Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada.
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.
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