AIM:The role of CD4+ Treg in immune responses has been well established. More recently, a role of CD8+ T regulatory cells (CD8 Treg) in the regulation of immune responses in health and autoimmune diseases has been investigated. Furthermore, different investigators have used different markers to define CD8 Treg. Finally, regulatory effects of CD8 Treg have been studied against T-cell responses; however, their role in regulating B-cell proliferation and immunoglobulin production has not been evaluated. Therefore, in this study we examined the effect of two types of CD8 Treg on B-cell proliferation and immunoglobulin production. METHODS:Purified CD8+ T cells were activated with anti-CD3/CD28 for 48 h and then sorted into two different types of CD8 Treg as defined by two different sets of markers, CD8+CD183+CD197+CD45RA- and CD8+CD183+CD25highCD278+. Purified B cells were cocultured with sorted CD8 Treg at 1:1, 1:1/2, and 1:1/4 ratios and activated with anti-CD40 and CpG. B-cell proliferation was assessed by the CFSE dye dilution assay and immunoglobulin production by the ELISA assay. RESULTS:Our data show CD183+CD197+CD45RA-CD8 Treg significantly inhibited B-cell proliferation and inhibited IgM and IgG production but not IgA production at 1:1 ratio only. However, CD183+CD25highCD278+CD8 Treg inhibited significantly B-cell proliferation at 1:1 and 1:1/2 ratios and IgM, IgG, and IgA production at all ratios. CONCLUSION:CD8 Treg regulate B-cell responses, and CD183+CD25highCD278+CD8 Treg are more powerful regulators of B-cell proliferation and immunoglobulin production than CD183+CD197+CD45RA-CD8 Treg and, therefore, may be used as preferred markers for CD8 Treg.