Unbalanced CD4⁺IL-10⁺ and more activated and exhausted CD8⁺ lymphocytes characterized patients with a major depressive episode

Depression is a highly prevalent psychiatric condition referred to as a major depressive episode (MDE). The underlying causes and mechanisms of depression remain poorly elucidated and, in consequence, the efficacy of the current therapies. Inflammation has been proposed to contribute to the pathophysiology of MDE with altered innate and adaptive immune responses. The present work aimed to shed light on the effector CD4⁺ T helper (Th) cell subsets response and the activation and exhaustion condition of CD8⁺ lymphocytes in the peripheral blood of patients with MDE. Patients with MDE (n = 57) and healthy controls (HCs) (n = 34) were recruited. The intracellular production of interferon (IFN) γ (Th1), interleukin (IL)-17 (Th17), and IL-10 (CD4⁺ IL-10⁺) as the activation and exhausted status of CD8⁺ lymphocytes were evaluated by flow cytometry. The frequencies of Th1 and Th17 cells did not show statistical differences, but a lower percentage of CD4⁺IL-10⁺ cells (P < 0.05) and CD4⁺IFNγ⁺IL-10⁺ cells (P < .01) were found in patients with MDE compared with HCs. The reduction in the CD4⁺IL-10⁺ and CD4⁺IFNγ⁺IL-10⁺ population negatively correlated with the number of depressive episodes (P < .05 and P < .01) and duration of illness (P < .01). A higher proportion of activated CD8⁺CD69⁺ (P < .0001) with potentially exhausted phenotype CD8⁺PD1⁺LAG3⁺ (P < .0001) were observed, which positively correlated with the severity, number of episodes, and duration of illness in MDE compared with HCs. Altogether, patients with MDE are characterized by unbalanced Th1/Th17/CD4⁺IL-10⁺ cells and increased activation and exhaustion of cytotoxic CD8⁺ T cells. Therapeutic strategies restoring this balance and effective control of inflammatory responses may be beneficial in MDE. SIGNIFICANCE STATEMENT: The pathophysiology of major depressive episode (MDE) remains poorly defined, hampering the development of more tailored therapeutic interventions. Inflammation has been proposed to initiate or maintain the MDE. This study demonstrates that effector CD4⁺ T helper cells are altered in MDE, showing a reduction in CD4⁺IL-10⁺ cells; meanwhile, CD8⁺ lymphocytes are more activated but with an exhausted phenotype. This study provides valuable insights into the lymphocyte response, which should lead to advances in the therapeutics of mood disorders.