Loss of Functional Suppression by CD4+CD25+ Regulatory T Cells in Patients with Multiple Sclerosis

Abstract

CD4+CD25+ regulatory T cells contribute to the maintenance of peripheral tolerance by active suppression because their deletion causes spontaneous autoimmune diseases in mice. Human CD4+ regulatory T cells expressing high levels of CD25 are suppressive in vitro and mimic the activity of murine CD4+CD25+ regulatory T cells. Multiple sclerosis (MS) is an inflammatory disease thought to be mediated by T cells recognizing myelin protein peptides. We hypothesized that altered functions of CD4+CD25hi regulatory T cells play a role in the breakdown of immunologic self-tolerance in patients with MS. Here, we report a significant decrease in the effector function of CD4+CD25hi regulatory T cells from peripheral blood of patients with MS as compared with healthy donors. Differences were also apparent in single cell cloning experiments in which the cloning frequency of CD4+CD25hi T cells was significantly reduced in patients as compared with normal controls. These data are the first to demonstrate alterations of CD4+CD25hi regulatory T cell function in patients with MS.

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

“…3B). These findings confirm recent observations by Viglietta et al [24], who tested T reg in a cohort of 15 MS patients using polyclonal stimulation with plate-bound anti-CD3 and found a consistently reduced suppressive effect mediated by CD4 + CD25 high T cells.…”

“…A similar subpopulation of CD4 + CD25 high T cells is present in human peripheral blood and lymphoid organs [6][7][8][9][10][11][12][13]. From a few recent studies, it appears that T reg numbers are reduced or their function is impaired in patients with various autoimmune disorders [17][18][19][20][21][22][23][24]. The impact of CD4 + CD25 high T cells in immunoregulation is critically supported by observations of Bennett et al [37] who demonstrated that mutations of Foxp3, a transcription factor which is essential for CD4 + CD25 high T cell function, cause the immune dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome (IPEX).…”

“…Viglietta et al [24] described an impaired inhibitory effect of polyclonally stimulated T reg from the peripheral blood of a small cohort of patients suffering from MS, a chronic inflammatory and predominantly demyelinating disease of the CNS. In murine experimental autoimmune encephalomyelitis, the mouse model for MS, myelin oligodendrocyte glycoprotein (MOG) has the highest capacity of inducing demyelination in mice [25].…”

CD4+ T cells from multiple sclerosis patients respond to a commensal‐derived antigen

“…This result is of potentially important clinical value since T reg function is known to be impaired in patients with MS 1, 2, 3. Since suppressive function often corresponds to the production of IL‐10, we next determined if stimulation with PSA resulted in an increase in IL‐10 production.…”

“…It is believed that the fluctuation between relapse and remission is greatly influenced by the balance of self‐reactive effector T cells and regulatory T cells (T regs ). Importantly, studies have shown that while MS patients harbor normal frequencies of T regs , their production of IL‐10 and overall suppressive capacity is significantly reduced allowing for increased inflammation driven by effector cells 1, 2, 3. For many years, the immunopathogenesis of this condition was attributed to an imbalance of Th1/Th2 polarization in which the enhanced Th1 response was associated with the production of IFN γ and TNF α .…”