Quantitative and qualitative normal regulatory T cells are not capable of inducing suppression in SLE patients due to T-cell resistance

Abstract

Previous reports have suggested that regulatory T cells (Treg) are abnormal in patients with systemic lupus erythematosus (SLE). In the present work, we quantified CD4+FOXP3+ Treg cells in patients with SLE and found no quantitative alterations. However, we found a clear defect in suppression assays. Surprisingly, SLE-derived Treg cells exhibited a normal phenotype and functional capacity. Conversely, SLE-derived CD4+CD25(-) effector T cells resisted suppression by autologous and allogeneic regulatory cells. Our findings strongly suggest that the defect in T-cell suppression observed in SLE is because of effector cell resistance and not because of an abnormal regulatory function.

Regulatory T Cell Deficiency in Systemic Autoimmune Disorders – Causal Relationship and Underlying Immunological Mechanisms

“…It was demonstrated that Teff cells isolated from lupus patients were less susceptible to Treg-mediated suppression [66,67], and the level of resistance inversely correlated with patients' clinical disease activities [67]. Similar findings have also been shown in several lupus-prone mouse strains [70,89,99].…”

“…Nevertheless, the identification of Foxp3, a relatively more specific if not exclusive marker of Treg, later allowed further verifications for the proposed link between Treg aberrations and systemic autoimmunity [49-51, 53, 57, 61, 68, 71, 73, 74, 76, 83, 88, 100]. However, there have also been controversial findings from other studies showing that the frequency of Treg cells, either defined as CD4 + CD25 bright or CD4 + Foxp3 + , could be normal www.intechopen.com [48,66,67,70,85,86] or even increased [47, 54-56, 58, 62-65, 69, 74, 76-79, 81] in lupus disease. Instead, some of these studies suggested that Treg were functionally defective and less capable of suppressing those potentially auto-reactive lymphocytes in lupus patients [44,48,53,57,59,60,66,76,80], and the mouse models [70,89,90].…”

“…These studies provided thus a plausible explanation for the systemic nature of the disease. A lack of Treg-mediated immune regulation in lupus is now a general consensus, although there have been differences in the findings as to whether a reduced Treg frequency [40-46, 49-53, 58-61, 68, 71-75, 82-84, 88, 90], defective Treg functions [44,48,53,57,59,60,66,70,76,80,89,90] or both, or alternatively an insensitivity of the Treg target cells [66,67,70,89,99], are truly accountable. By using CD25 as the marker, an early study by Crispin and colleagues first showed that, in lupus patients with active disease, the frequencies of Treg (CD4+CD25 +/bright ) were significantly decreased, while T cells with an activated T helper (Th) effector phenotype (CD4 + CD69 + ) increased [40].…”

“…However, there have also been controversial findings from other studies showing that the frequency of Treg cells, either defined as CD4 + CD25 bright or CD4 + Foxp3 + , could be normal www.intechopen.com [48,66,67,70,85,86] or even increased [47, 54-56, 58, 62-65, 69, 74, 76-79, 81] in lupus disease. Instead, some of these studies suggested that Treg were functionally defective and less capable of suppressing those potentially auto-reactive lymphocytes in lupus patients [44,48,53,57,59,60,66,76,80], and the mouse models [70,89,90]. Again, alternative findings demonstrating lupus Treg being functionally normal [49,50,62,67,85], or at least normal in majority of patients tested [48,64], or even enhanced in some way [68,80,87] added further confusion as well as interest to the matter.…”

Lys63-polyubiquitination by the E3 ligase casitas B-lineage lymphoma-b (Cbl-b) modulates peripheral regulatory T cell tolerance in patients with systemic lupus erythematosus

“…In murine models and humans, quantitative and functional alterations in T regs have been related to the development and maintenance of many organ-specific and systemic autoimmune diseases [2, [8][9][10][11][12][13][14][15][16]. In particular, defects in FOXP3 gene, IL-2Ra signalling pathway and inhibitory markers, such as cytotoxic T lymphocyteassociated protein-4 (CTLA-4) or programmed cell death protein-1 (PD-1), as well as over-expression of T-bet or signal transducer and activator of transcription-3 (STAT-3), appear to be critical in the loss of suppressive function or stability in different T helper type 1 (Th1)-and Th17-dominated autoimmune settings, such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus (SLE) [17].…”