Aberrant T-cell exhaustion in SCID survivors with poor T-cell reconstitution post transplant
The Journal of allergy and clinical immunology
(HCT); (SCID); T-cell exhaustion; conditioning chemotherapy; hematopoietic cell transplantation; immune reconstitution; severe combined immunodeficiency
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.
Labrosse, Roxane; Boufaied, Ines; Bourdin, Benoîte; Gona, Saideep; Randolph, Haley E.; Logan, Brent R.; Bourbonnais, Sara; Berthe, Chloé; Chan, Wendy; Buckley, Rebecca H.; Parrott, Roberta E.; Cuvelier, Geoffrey D.; Kapoor, Neena; Chandra, Sharat; Dávila Saldaña, Blachy J.; Eissa, Hesham; Goldman, Fred D.; Heimall, Jennifer; O'Reilly, Richard; Chaudhury, Sonali; Kolb, Edward A.; Shenoy S, Shalini; Griffith, Linda M.; Pulsipher, Michael; Kohn, Donald B.; Notarangelo, Luigi D.; Pai, Sung-Yun; Cowan, Morton J.; Dvorak, Christopher C.; Haddad, Élie; Puck, Jennifer M.; and Barreiro, Luis B., "Aberrant T-cell exhaustion in SCID survivors with poor T-cell reconstitution post transplant" (2022). GW Authored Works. Paper 1470.