Fine-Tuning of Regulatory T Cell Function: The Role of Calcium Signals and Naive Regulatory T Cells for Regulatory T Cell Deficiency in Multiple Sclerosis

Abstract

The suppressor function of regulatory T cells (Tregs) is impaired in multiple sclerosis (MS), but the mechanisms underlying this deficiency are not fully understood. As Tregs counteract the sustained elevation of intracellular calcium, which is indispensable for full activation of conventional T cells (Tcons), we hypothesized that interference with this pathway might prompt MS-related Treg dysfunction. Using single-cell live imaging, we observed that Tregs rapidly reduce Ca2+ influx and downstream signals in Tcons upon cell contact, yet differ in their potency to efficiently suppress several target cells at the same time. Strikingly, individual Tregs harboring a CD4+CD25+FOXP3+CD45RA+ naive phenotype suppressed significantly more adjacent Tcons than did CD4+CD25+FOXP3+CD45RA− memory Tregs. Some constituents even completely failed to dampen Tcon Ca2+ influx and were contained exclusively in the memory subset. In accordance with their more powerful suppressive performance, the Ca2+ signature was considerably enhanced in naive Tregs in response to TCR triggering, compared with the memory counterparts. MS Tregs displayed a significantly diminished suppression of mean Ca2+ influx in the sum of individual Tcons recorded. This reduced inhibitory activity was closely linked to decreased numbers of individual Tcons becoming suppressed by adjacent Tregs and, in turn, correlated with a marked reduction of naive subtypes and concomitant expansion of nonsuppressive memory phenotypes. We conclude that the superior achievement of naive Tregs is pivotal in maintaining Treg efficiency. As a consequence, MS Tregs become defective because they lack naive subtypes and are disproportionately enriched in memory cells that have lost their inherent downregulatory activity.

Sequential monitoring of lymphocyte subsets and of T-and-B cell neogenesis indexes to identify time-varying immunologic profiles in relation to graft-versus-host disease and relapse after allogeneic stem cell transplantation

“…This apparently contradictory finding was rarely reported before [5,7]. Several studies have been performed in murine models of GVHD, or in transplanted patients without distinction among Treg subsets, which display different regulatory efficiency [47]. Treg EM seem less effective than naïve Treg, since naïve Treg may directly inhibit effector T cells and APC in lymphoid tissues, which are of critical relevance for induction and suppression of GVH reactions [48,49].…”

GM-CSF induces neuroprotective and anti-inflammatory responses in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxicated mice

“…Among adaptive immune changes, increased presence of T effector memory cells (Tem) and dysfunctional regulatory T cells (Treg) are seen during PD progression (Hutter Saunders et al, 2012). Similar altered profiles of effector T cell (Teff) and dysregulated Treg are seen in a range of disorders that include multiple sclerosis, stroke, Crohn’s disease, type 1 diabetes, rheumatoid arthritis, and myasthenia gravis (Balandina et al, 2005, Fletcher et al, 2009, Ishikawa et al, 2013, Nie et al, 2013, Schwarz et al, 2013). Based on these data, we reasoned that the induction of Treg could correct such immune aberrations.…”

Peripherally Induced Regulatory T Cells: Recruited Protectors of the Central Nervous System against Autoimmune Neuroinflammation

“…Other surface molecules expressed by Treg cells that have been shown to modulate immune suppression include Neuropilin-1, LAG-3, TIM-3, and TIGIT (126–137). Human Treg cells also suppress effector T cells by interfering with Ca2 + signaling in effector T cells and this suppressor function appears to be defective in Treg cells in some MS patients as well (134, 136, 138, 139). In addition to various functional deficits, the Treg cells found in MS patients may acquire the proinflammatory phenotype of effector T cells.…”