An Act of Balance Between Adaptive and Maladaptive Immunity in Depression: a Role for T Lymphocytes

Abstract

Historically the monoaminergic neurotransmitter system, in particular the serotonergic system, was seen as being responsible for the pathophysiology of major depressive disorder (MDD). With the advent of psychoneuroimmunology an important role of the immune system in the interface between the central nervous systems (CNS) and peripheral organ systems has emerged. In addition to the well-characterised neurobiological activities of cytokines, T cell function in the context of depression has been neglected so far. In this review we will investigate the biological roles of T cells in depression. Originally it was thought that the adaptive immune arm including T lymphocytes was excluded from the CNS. It is now clear that peripheral naïve T cells not only carry out continuous surveillance within the brain but also maintain neural plasticity. Furthermore animal studies demonstrate that regulatory T lymphocytes can provide protection against maladaptive behavioural responses associated with depression. Psychogenic stress as a major inducer of depression can lead to transient trafficking of T lymphocytes into the brain stimulating the secretion of certain neurotrophic factors and cytokines. The separate and combined mechanism of CD4 and CD8 T cell activation is likely to determine the response pattern of CNS specific neurokines and neurotrophins. Under chronic stress-induced neuroinflammatory conditions associated with depression, T cell responses may become maladaptive and can be involved in neurodegeneration. Additionally, intracellular adhesion and MHC molecule expression as well as glucocorticoid receptor expression within the brain may play a role in determining T lymphocyte functionality in depression. Taken together, T lymphocyte mechanisms, which confer susceptibility or resilience to MDD, are not yet fully understood. Further insight into the cellular and molecular mechanisms which balance the adaptive and maladaptive roles of T lymphocytes may provide a better understanding of both the neuro- degenerative and -regenerative repair functions as present within the neuroimmune network during depression. Furthermore T cells may be important players in restoration of normal behaviour and immune cell homeostasis in depression.

Altered populations of natural killer cells, cytotoxic T lymphocytes, and regulatory T cells in major depressive disorder: Association with sleep disturbance

“…A similar impairment of the adaptive immune response has been reported in depression, in particular, decreases in NKC cytotoxicity and reduced mitogen-stimulated T-lymphocyte proliferation (Blume et al, 2011; Irwin and Miller, 2007; Miller, 2010; Toben and Baune, 2015; Zorrilla et al, 2001). Consistent with these data, depressed individuals show a decreased response to viral vaccines (Irwin et al, 1998; Irwin et al, 2013), and reportedly, a worse prognosis in cases of infectious disease (Leserman, 2008) and cancer (Sephton et al, 2009).…”

“…This perspective evolved from the stress literature which demonstrated that chronic psychological stressors were associated with declines in the total numbers of circulating B-cells and T-cells, reduced mitogen-induced lymphocyte proliferation and natural killer cell (NKC) activity, and the mobilization of regulatory T-cells (T reg ), along with greater susceptibility to viral infections, reduced immune responses to vaccines, reactivation of latent herpesviruses, and slowed wound healing (Dhabhar, 2014; Glaser and Kiecolt-Glaser, 2005; Irwin, 2008; Toben and Baune, 2015). This impairment in the adaptive immune response is hypothesized to be mediated by the suppressive effects of cortisol on the expression of anti-viral genes as well as the effects of adrenergic signaling on the expression of type I interferons (Irwin and Cole, 2011).…”

A dynamic course of T cell defects in individuals at risk for mood disorders

“…Lately, some excellent reviews on the role of T cells in mood disorders have been published (7) (8) (9). T cells are essential for antigen-specific cell-mediated immune responses.…”

“…The present idea is that in patients with an active mood disorder a pro-inflammatory state prevails with raised numbers of T h 17 cells and reduced numbers of T regs , while in mood disorder patients in remission/recovery normal number of T cells can be found. Yet T cells seems to have an impaired capability for expansion and an increased apoptosis when stimulated with a mitogen (9).…”

Duality of Antidepressants and Neuroprotectants

“…In addition to neurotrophic factors, important roles for inflammatory mediators are evident in pathophysiology of a variety of neuropsychiatric disorders including MDD (Felger and Lotrich 2013; Postal and Appenzeller 2015; Toben and Baune 2015). This is supported by the results of numerous studies indicating elevated levels of the pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β in plasma of depressed patients (Gold and Irwin 2009; Felger and Lotrich 2013; Toben and Baune 2015).…”