High frequency of CD95⁺/CD45RA^- regulatory T cells defines an immunosuppressive profile associated with MDS...

Dynamic interactions between mutated haematopoietic cells and immune cells are key drivers of myelodysplastic neoplasms (MDS) initiation and progression. Regulatory T cells (Tregs) are central mediators of immunosuppression in MDS. We thus aimed to characterize Treg subpopulations in the bone marrow (BM) of MDS patients and to explore their clinical significance. Using mass cytometry and an unbiased multidimensional analytical approach, we first confirmed the presence in MDS BM of two Treg subsets, including the highly activated CD95⁺/CD45RA^- subpopulation previously reported in aplastic anaemia. We then prospectively analysed Tregs distribution in BM of 113 MDS patients at diagnosis and during follow-up. While Treg proportions among CD4⁺ T cells were unchanged, CD95⁺/CD45RA^- Tregs were significantly expanded in the BM of both low- and high-risk MDS patients. CD95⁺/CD45RA^- Tregs accumulated during disease evolution but remained stable in patients responding to hypomethylating agents. At diagnosis, CD95⁺/CD45RA^- Tregs levels correlated with specific clinical features: low CD95⁺/CD45RA^- Tregs with TET2/IDH mutations and autoimmune manifestations; high CD95⁺/CD45RA^- Tregs with an increased risk of disease progression independently of the IPSS-R and the IPSS-M. Our findings suggest that profiling Treg subpopulations at diagnosis could improve MDS risk stratification and guide immunosuppressive therapeutic decisions.