Discussion
Remission in SLE implies absence of major signs and symptoms, which translate into a lower probability of adverse outcomes when this state is sustained. In 2016, the conclusions from an international consensus of experts on the definitions of remission in SLE (DORIS) were published [12]. It was established that to catalog a patient in remission it is important to rely on activity indices (as SLEDAI, BILAG or ECLAM). The consensus also highlights the importance of differentiating patients in remission who are under treatment (low doses of glucocorticoids, maintenance immunosuppressants and/or biological maintenance) from those without treatment (or with antimalarials). All the patients classified and included as in remission in this study, had a sustained clinical SLEDAI of 0, and were free of medication, including antimalarials for at least 10 years.
Patients with SLE, even after achieving remission for a long time, are not considered cured, and there is evidence confirming a subjacent autoimmune response: presence of autoantibodies or low complement [8] or relapses after long periods in remission (over 10 years) [13]. How the altered immune response is kept under control in patients with lupus that achieve remission is not understood and understudied. Our results support T cell exhaustion as a contributor in this process.
Using an unsupervised flow cytometric analysis, we found that multiple populations that express markers that have been associated with T cell exhaustion like PD-1, CD57 and EOMES are altered in patients with SLE when compared with HS. Remarkably, not all the populations with markers of exhaustion were different between SLE patients and HS, finding consistent with previous reports, that suggest that opposed to what occurs in models of chronic viral infection, patients with autoimmune disease have a selective upregulation of exhaustion associated receptors [6]. This phenomenon suggests that the signals that induce exhaustion in each condition are somehow context specific.
Exhausted T cells have a differential transcriptome and epigenome when compared with effector T cells [14, 15], and exhaustion is considered a stable differentiation fate of T cells, even though it can be reversed by therapeutic interventions. The presence of exhausted T cells in patients with an active autoimmune disease, suggests that cells that are activated by an ongoing inflammatory response or by the persistent presence of an autoantigen, cannot get costimulatory signals above certain threshold, and are acquiring an exhausted phenotype [16]. The function of these cells is not completely known, but in patients with cancer, exhausted cells in the tumor microenvironment contribute with the tumor immune evasion, or induced tumor tolerance. This deleterious effect in cancer might have a positive implication in other diseases, when tolerance has a positive connotation, as transplantation and autoimmunity [17].
In patients with autoimmune diseases, T cell exhaustion has been associated more with the progression than with the onset of the disease [6, 18]. In this regard, this is the first study that identifies specific subpopulations of exhausted T cells in patients with lupus in long-term remission.
The mechanisms underlying the hyporesponsive state of exhausted cells are also subject of study. We found an increased frequency of CD4 and CD8 EOMES+ cells in patients in remission. This transcription factor, member of the T-bet family, has also been described as altered in chronic viral infection [19] and cancer [20]. Remarkably, in patients with cancer, EOMES is necessary for the induction of cytotoxic anti-tumor T cells, however, the deletion of one allele of this transcript factor reduced the number of exhausted T cells and improved tumor control [20]. This dual effect emphasizes the fine tuning involved in the generation of an exhausted versus effector response in T cells. A deeper understanding of the mechanisms that induce exhaustion of specific populations of T cells that are pathogenic in patients with SLE, might represent a potential therapeutic tool that will contribute to the goal of achieving sustained remission.
There are some limitations of this study. The study is transversal, however, to identify and study longitudinally patients in long-term remission free of medication before they achieve this status is probably not feasible. We believe this group of patients provides an ideal group for this analysis, as there is no confounding effect caused by medications and there is no recent evidence of disease activity. We studied a relatively reduced number of markers associated with exhaustion, however, these were carefully selected and allowed us to identify populations that were differentially present in the groups of interest.
Our results confirm the presence of certain subpopulations of exhausted T-cells in patients in lupus that are unequivocally in remission. This suggests a potential role of T-cell exhaustion as a mechanism of tolerance in patients with SLE. The populations identified in the present study warrant further investigation as prognostic markers in longitudinal studies of these patients, and in independent cohorts. The identification of the specific mechanisms behind the origin of these populations might provide new therapeutic options in SLE.