Exhausted T cells in systemic lupus erythematosus patients in long-standing remission

摘要

The mechanisms that drive systemic lupus erythematosus (SLE) patients to achieve remission are unknown; one possible explanation might be T cell exhaustion. 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. 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 programmed cell death 1 (PD)-1, T cell immunoglobulin and mucin 3 (Tim-3), natural killer cell receptor (2B4), eomesodermin (EOMES) and T-box transcription factor TBX21 (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. 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(+)T-bet(+)CD45RO(+) cells identified in the unsupervised analysis were significantly increased in PR-SLE versus Act-SLE [median = 0 center dot 20, interquartile range (IQR) = 1 center dot 74-30 center dot 50 versus 1 center dot 68, IQR = 0 center dot 4-2 center dot 83; P versus Act-SLE (5 center dot 24, IQR = 3 center dot 38-14 center dot 70 versus 1 center dot 39, IQR = 0 center dot 48-2 center dot 87; P < 0 center dot 001). CD8(+)EOMES(+) cells were increased in PR-SLE versus Act-SLE (37 center dot 6, IQR = 24 center dot 9-53 center dot 2 versus 8 center dot 13, IQR = 2 center dot 33-20 center dot 5; P < 0 center dot 001). Exhausted and activated T cells presented an increased frequency of PD-1, CD57 and EOMES in SLE patients versus healthy subjects. 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.