T Cell Exhaustion in Patients with Severe Combined Immunodeficiency Transplanted Without Conditioning or Graft-Versus-Host Disease Prophylaxis: The Duke Experience

Introduction Our large cohort of patients with severe combined immunodeficiency (SCID) underwent bone marrow transplantation (BMT) without pre-transplant conditioning or graft-versus-host disease prophylaxis and has an overall survival exceeding 70% at 43 years of follow-up. It is important to determine whether immune reconstitution in these patients is sufficient for normal life expectancy. Methods Flow cytometry was performed to longitudinally study the reconstitution of CD4 and CD8 T cells among 59 patients with different molecular types of SCID at Duke for up to 30 years post-BMT. The flow cytometry panel was optimized to identify and quantify both PD-1+CD57+ senescent and PD-1+CD57- exhausted T cells. Results Data collection occurred at various time points and was not consistent across the cohort with median (min, max) number of samples per patient being 2 (1, 7). We found a strong negative correlation between the CD4 T cell count and percentage of CD4 exhausted T cells (ρ = -0.67, confidence interval [CI]: -0.56 to -0.76, p < 0.001) and a moderate negative correlation between the CD4 T cell count and the percentage of CD8 exhausted T cells (ρ = -0.48, CI: -0.34 to -0.60, p < 0.001). Through an unadjusted regression, we found that each additional year from time of transplant was associated with a mean increase in the percentage of CD4 exhausted T cells by 0.7 (CI: 0.4 to 1.0, p < 0.001). Recipients of HLA-identical BMT had less CD4 and CD8 exhaustion. Conclusions and Ongoing Work We identified a negative correlation between CD4 T cell counts and the accumulation of exhausted T cells in a Duke cohort of 59 patients with SCID. Ongoing work aims to characterize the factors that might contribute to T cell exhaustion, including peri-transplant course, infections, molecular type of SCID, degree of T cell immune reconstitution, and impact of aging in comparison to healthy controls. Examining the mechanisms and relevant variables contributing to T cell exhaustion may help improve long-term transplant outcomes for SCID as well as other diseases requiring hematopoietic stem cell transplantation.