Targeting the Adaptive Immune System in Depression: Focus on T Helper 17 Cells

Abstract

There is a vital need to understand mechanisms contributing to susceptibility to depression to improve treatments for the 11% of Americans who currently suffer from this debilitating disease. The adaptive immune system, comprising T and B cells, has emerged as a potential contributor to depression, as demonstrated in the context of lymphopenic mice. Overall, patients with depression have reduced circulating T and regulatory B cells, "immunosuppressed" T cells, and alterations in the relative abundance of T cell subtypes. T helper (Th) cells have the capacity to differentiate to various lineages depending on the cytokine environment, antigen stimulation, and costimulation. Regulatory T cells are decreased, and the Th1/Th2 ratio and the Th17 cells are increased in patients with depression. Evidence for changes in each Th lineage has been reported to some extent in patients with depression. However, the evidence is strongest for the association of depression with changes in Th17 cells. Th17 cells produce the inflammatory cytokine interleukin (IL)-17A, and the discovery of Th17 cell involvement in depression evolved from the well established link that IL-6, which is required for Th17 cell differentiation, contributes to the onset, and possibly maintenance, of depression. One intriguing action of Th17 cells is their participation in the gut-brain axis to mediate stress responses. Although the mechanisms of action of Th17 cells in depression remain unclear, neutralization of IL-17A by anti-IL-17A antibodies, blocking stress-induced production, or release of gut Th17 cells represent feasible therapeutic approaches and might provide a new avenue to improve depression symptoms. SIGNIFICANCE STATEMENT: Th17 cells appear as a promising therapeutic target for depression, for which efficacious therapeutic options are limited. The use of neutralizing antibodies targeting Th17 cells has provided encouraging results in depressed patients with comorbid autoimmune diseases.

Fig. 1

The adaptive immune system. It includes T (CD4⁺ and CD8⁺) and B cells. CD8⁺ T cells differentiate into cytotoxic T cells after recognizing antigen presented by MHC class I. CD4⁺ T cells in contrast recognize antigens presented by MHC class II on antigen-presenting cells. Once activated by their antigen and the cytokine milieu (each lineage of CD4⁺ T cells has a combination of cytokines required to differentiate), as well as upon receiving costimulatory signals, CD4⁺ T cells differentiate in the different lineages: Treg, Th1, Th2, and Th17 cells, which produce a combination of cytokines as indicated. Finally, CD4⁺ T cells help B cells to differentiate into plasma cells once they encounter a specific antigen and plasma cells produce antigen specific antibodies.

Fig. 2

Potential mechanisms whereby Th17 cells promote depressive symptoms. Upon stress, Th17 cells enter the brain. CCR6 and IL-17A seem critical for the entry of pathogenic Th17 cells into the brain after stress. Various effects of Th17 cells have been proposed in the brain. Neurons, microglia, and astrocytes express IL-17RA and are therefore regulated by the Th17 cell signature cytokine IL-17A. In astrocytes, for example, IL-17A activates glutamate excitotoxicity. IL-17A also inhibits neurogenesis. Th17 cells have also been reported to trigger neuronal cell death via direct contact leading to increased intracellular Ca²⁺ level or through activation of neuronal Fas by FasL produced by Th17 cells.

Fig. 3

Effects of glucocorticoids, catecholamines, and microbiota on T helper cells.

Fig. 4

Overall selection of T cells associated with depression. Glucocorticoid treatment and microbiota alterations in depression have been associated with a shift toward Th17 cells. Catecholamines seem to favor Th2 cells. However, catecholamines promote T helper cell activation, whereas they block leukocyte migration. Antidepressant treatments in contrast seem to reduce T helper cells in a nonspecific manner and favor regulatory T cells.