Background: In a previous study, we found an up-regulated inflammatory monocyte gene expression profile in major depressive disorder (MDD) patients aged >= 28 years and a down-regulated inflammatory gene expression profile in MDD patients aged <28 years. In the same sample of patients, we aimed to investigate immune dysregulation in the lymphocyte arm of the immune system, particularly in the context of the described monocyte (de-)activation states. Methods: From deep frozen leukocytes, circulating percentages of monocytes, lymphocytes, B, T, and natural killer (NK) cells, and various functional subsets of T and T helper (T-h) cells (T(h)1, T(h)2, T(h)17, and natural T regulatory cells) were measured in N = 50 MDD patients and N = 58 age- and gender-matched healthy controls (HC). In addition, serum levels of interleukin (IL)-6, sCD25, IL-7, IL-3, SCF, IGF-BP2, and EGF were evaluated. Results: MDD patients were in general characterized by an impaired maturation of Th2 cells, Th17 cells, and NK cells and by decreased serum levels of IL-7 and sCD25. MDD patients aged >= 28 years additionally exhibited decreased percentages of CD4(+)CD25(high)FoxP3(+) T regulatory cells, next to signs of the above described partial T cell defects. Natural T regulatory cells were inversely associated with the pro-inflammatory state of the monocytes (r = -.311; p = .034) that characterized this patient subgroup. Conclusions: Deficiencies of the NK and T (regulatory) cell system and inflammatory monocyte immune activation co-occur as partly interrelated phenomena within the same MDD patients. (C) 2015 Elsevier Inc. All rights reserved.