Human CD4+ T cells can be classified as either naive, central memory (T-CM), or effector memory (T-EM) cells. To identify the CD4+ T cell subsets most important in the pathogenesis of rheumatoid arthritis (RA), we phenotypically defined human CD4+ T cells as functionally distinct subsets, and analyzed the distribution and characteristics of each subset in the peripheral blood. We classified CD4+ T cells into six novel subsets based on the expression of CD45RA, CCR7, CD27, and CD28. The CCR7 + CD45RA-CD27 + CD28+ T-CM subset comprised a significantly smaller proportion of CD4+ T cells in RA patients compared to healthy controls. The frequency of TNF-alpha-producing cells in the CCR7-CD45RA-CD27 + CD28+ T-EM subset was significantly increased in RA. Furthermore, within the CCR7 + CD45RA-CD27 + CD28+ T-CM subset, which was decreased in periperal blood from RA, the proportions of total Foxp3+ Treg cells and CD45RA-Foxp3(high) activated/effector Treg cells were significantly lower in RA patients. Our findings suggest that the increased proportion of TNF-alpha-producing cells and the decreased proportion of CD45RA-Foxp3(high) activated/effector Treg cells in particular subsets may have critical roles in the pathogenesis of RA. (C) 2013 Elsevier Inc. All rights reserved.