Dynamics of T cell repertoire renewal following autologous hematopoietic stem cell transplantation in multiple sclerosis

Autologous hematopoietic stem cell transplantation (aHSCT) is a highly effective treatment of multiple sclerosis (MS). It depletes autoreactive cells and subsequently renews adaptive immune cells. The possible proinflammatory potential of surviving T cells early after aHSCT has not been studied. Here, we examined the dynamics of new and surviving T cells in 27 patients after aHSCT by multidimensional flow cytometry, T cell receptor (TCR) sequencing, specificity testing, telomere length profiling, and HLA genotyping. Early after aHSCT, naive T cells are barely detectable, whereas effect or memory (EM) T cells quickly reconstitute to pre-aHSCT values. EM CD4(+) T cells early after aHSCT have shorter telomeres, have higher expression of senescence and exhaustion markers, and proliferate less than those before aHSCT. We find a median TCR repertoire overlap of 26% between the early post-aHSCT EM CD4(+) T cells and pre-aHSCT, indicating persistence of EM CD4(+) T cells early after transplantation. The EM CD4(+) TCR repertoire overlap declines to 15% at 12 months after aHSCT, whereas the naive TCR repertoire entirely renews. HLA-DR-associated EM CD4(+) T cell reactivity toward MS-related antigens decreased after aHSCT, whereas reactivity toward EBV increased. Our data show substantial survival of pre-aHSCT EM CD4(+) T cells early after transplantation but complete renewal of the T cell repertoire by nascent T cells later.

Automated summary

Autologous hematopoietic stem cell transplantation (aHSCT) is a highly effective treatment for multiple sclerosis (MS), renewing adaptive immune cells. The dynamics of T cells after aHSCT were examined in this study. The results showed that naive T cells were barely detectable early after aHSCT, while effect or memory (EM) T cells quickly reconstituted. EM CD4(+) T cells early after aHSCT exhibited shorter telomeres and higher expression of senescence and exhaustion markers. The T cell receptor (TCR) repertoire overlap between early post-aHSCT EM CD4(+) T cells and pre-aHSCT declined over time, indicating the renewal of the T cell repertoire by nascent T cells. The reactivity of HLA-DR-associated EM CD4(+) T cells towards MS-related antigens decreased after aHSCT, while reactivity towards Epstein-Barr virus (EBV) increased.