Introduction The mechanisms that drives SLE remission.The aim of the present study was to measure CD4+ and CD8+ T cell exhaustion in SLE patients in prolonged remission (PR-SLE) and compared them with patients with active SLE (Act-SLE) and healthy subjects Methods We included 15 PR-SLE patients, 15 Act-SLE and 29 healthy subjects. T-cell exhaustion was determined by flow cytometry according to the expression of PD-1, Tim-3, 2B4, EOMES and T-bet in CD4+ and CD8+ T cells. Dimensionality reduction using the t-Distributed Stochastic Neighbor Embedding algorithm and Clustering Analysis was used for the identification of relevant populations. Results Percentages of CD3+, CD4+ and CD8+ T cells were similar among groups. We identified five subpopulations of CD8+ and seven of CD4+ cells. The CD4+Tbet+CD45RO+ cells identified in the unsupervised analysis were significantly increased in PR-SLE vs Act-SLE (median: 10.20, IQR: 1.74-30.50 vs. 1.68, IQR: 0.4-2.83; p<0.01). CD4+EOMES+ cells were also increased in PR-SLE vs Act-SLE (5.24, IQR: 3.38-14.70 vs. 1.39, IQR: 0.48-2.87; p<0.001). CD8+ EOMES+ cells were increased in PR-SLE vs Act-SLE (37.6, IQR: 24.9-53.2 vs 8.13, IQR: 2.33-20.5; p<0.001). Exhausted and activated T cells presented an increased frequency of PD-1, CD57 and EOMES in SLE patients vs healthy subjects. Conclusions Some subpopulations of T cells expressing markers associated with exhaustion are increased in patients in remission, supporting T-cell exhaustion as a tolerance mechanism in SLE. Exhaustion of specific populations of T cells might represent a potential therapeutic tool that will contribute to the goal of achieving sustained remission in these patients.