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Objective<p>Autoimmune lymphoproliferative syndrome (ALPS) with FAS mutation (ALPS-FAS) is a nonmalignant, noninfectious, lymphoproliferative disease with autoimmunity. Given the central role of natural regulatory T cells (nTregs) in the control of lymphoproliferation and autoimmunity, we assessed nTreg-suppressive function in 16 patients with ALPS-FAS.</p>Results<p>The proportion of CD25^highCD127^low Tregs was lower in ALPS-FAS patients than in healthy controls. This subset was correlated with a reduced CD25 expression in CD3⁺CD4⁺ T cells from ALPS patients and thus an abnormally low proportion of CD25^highFOXP3⁺ Helios⁺ T cells. The ALPS patients also displayed a high proportion of naïve Treg (FOXP3^lowCD45RA⁺) and an unusual subpopulation (CD4⁺CD127^lowCD15s⁺CD45RA⁺). Despite this abnormal phenotype, the CD25^highCD127^low Tregs’ suppressive function was unaffected. Furthermore, conventional T cells from FAS-mutated patients showed normal levels of sensitivity to Treg suppression.</p>Conclusion<p>An abnormal Treg phenotype is observed in circulating lymphocytes of ALPS patients. However, these Tregs displayed a normal suppressive function on T effector proliferation in vitro. This is suggesting that lymphoproliferation observed in ALPS patients does not result from Tregs functional defect or T effector cells insensitivity to Tregs suppression.