HLA-DR⁺ Tregs and HLA-DR⁻ Tregs have distinct mechanisms of suppression. HLA-DR⁺ Tregs directly inhibit both proliferation and cytokine suppression through a cell-contact dependent mechanism, while HLA-DR⁻ Tregs induce secretion of IL-4 and IL-10 in Tresp before suppressing proliferation.

CD4⁺CD25^high cells isolated from patients with MS suppress less efficiently than Tregs purified from healthy donors. CD4⁺CD25⁻ responder T cells and CD4+CD25high cells from six MS patients and six normal controls were stimulated with soluble anti-CD3 and anti-CD28 (5μg/ml) alone or cocultured at different responder/suppressor rations (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 (open sircles) and healthy controls (closed squares). (Reprint permission from J. Exp. Med.)