fig5: The proliferative response in both patients and healthy controls is suppressed in cultures receiving T cell receptor signals of different natures. CD4+CD25− responder T cells and CD4+CD25hi cells from six MS patients and six normal controls were stimulated with soluble anti-CD3 and anti-CD28 (5 μg/ml) alone or cocultured at different responder/suppressor ratios (1:1, 1:1/2, and 1:1/4). The average proliferative response was 13,494 cpm in the patient group and 15,974 cpm in the control group. The percent inhibition of coculture proliferation was calculated in patients with MS (○) and healthy controls (▪).

Mentions: We have shown previously that a qualitatively different stimulus, such as soluble anti-CD3 and anti-CD28, induced lower levels of responder T cell proliferation as compared with plate-bound anti-CD3 and, thus, was more significantly inhibited upon coculture with CD4+CD25hi. It was of interest to examine whether differences in suppressor function by CD4+CD25hi cells between patients with MS and control subjects would be observed with qualitative changes in TCR signaling. Cocultures of regulatory and responder T cells from patients and controls were stimulated with soluble anti-CD3 and anti-CD28. As expected, the magnitude of the proliferative response was significantly lower than that obtained with plate-bound anti-CD3 from the same individual. The CD4+CD25− T cells isolated from patients and controls responded similarly to this stimulus. Yet, in contrast to plate-bound anti-CD3, the qualitatively different TCR signal delivered by soluble anti-CD3 and anti-CD28 allowed the appearance of suppressor function by cocultured CD4+CD25hi regulatory T cells derived from patients with MS, particularly at higher ratio of regulatory T cells in the culture (Fig. 5).

Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA - J. Exp. Med. (2004)

Bottom Line: 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.

Affiliation: Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

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.