Christina Ruland

Altered adaptive immunity involving T lymphocytes has been found in depressed patients and in stress-induced depression-like behavior in animal models. Peripheral T cells play important roles in homeostasis and function of the central nervous system and thus modulate behavior. However, the T cell phenotype and function associated with susceptibility and resilience to depression remain largely unknown. Here, we characterized splenic T cells in susceptible and resilient mice after 10 days of social defeat stress (SDS). We found equally decreased T cell frequencies and comparably altered expression levels of genes associated with T helper (Th) cell function in resilient and susceptible mice. Interleukin (IL)-17 producing CD4⁺ and CD8⁺ T cell numbers in the spleen were significantly increased in susceptible mice. These animals further exhibited significantly reduced numbers of regulatory T cells (T_reg) and decreased gene expression levels of TGF-β. Mice with enhanced Th17 differentiation induced by conditional deletion of PPARγ in CD4⁺ cells (CD4-PPARγ^KO), an inhibitor of Th17 development, were equally susceptible to SDS when compared to CD4-PPARγ^WT controls. These data indicate that enhanced Th17 differentiation alone does not alter stress vulnerability. Thus, SDS promotes Th17 cell and suppresses T_reg cell differentiation predominantly in susceptible mice with yet unknown effects in immune responses after stress exposure.

Environmental factors, such as housing conditions and cognitively stimulating activities, have been shown to affect behavioral phenotypes and to modulate neurodegenerative conditions such as Alzheimer's disease (AD). AD is a progressive neurodegenerative disorder affecting cognitive functions. Epidemiological evidence and experimental studies using rodent models have indicated that social interaction reduces development and progression of disease. Drosophila models of Aβ42‐associated AD lead to AD‐like phenotypes, such as long‐term memory impairment, locomotor and survival deficits, while effects of environmental conditions on AD‐associated phenotypes have not been assessed in the fly. Here, we show that single housing reduced survival and motor performance of Aβ42 expressing and control flies. Gene expression analyses of Aβ42 expressing and control flies that had been exposed to different housing conditions showed upregulation of Iron regulatory protein 1B (Irp‐1B) in fly brains following single housing. Downregulating Irp‐1B in neurons of single‐housed Aβ42 expressing and control flies rescued both survival and motor performance deficits. Thus, we provide novel evidence that increased cerebral expression of Irp‐1B may underlie worsened behavioral outcome in socially deprived flies and can additionally modulate AD‐like phenotypes.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). It affects more than two million people worldwide, mainly young adults, and may lead to progressive neurological disability. Chemokines and their receptors have been shown to play critical roles in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a murine disease model induced by active immunization with myelin proteins or transfer of encephalitogenic CD4⁺ T cells that recapitulates clinical and neuropathological features of MS. Chemokine ligand-receptor interactions orchestrate leukocyte trafficking and influence multiple pathophysiological cellular processes, including antigen presentation and cytokine production by dendritic cells (DCs). The C-C class chemokines 17 (CCL17) and 22 (CCL22) and their C-C chemokine receptor 4 (CCR4) have been shown to play an important role in homeostasis and inflammatory responses. Here, we provide an overview of the involvement of CCR4 and its ligands in CNS autoimmunity. We review key clinical studies of MS together with experimental studies in animals that have demonstrated functional roles of CCR4, CCL17, and CCL22 in EAE pathogenesis. Finally, we discuss the therapeutic potential of newly developed CCR4 antagonists and a humanized anti-CCR4 antibody for treatment of MS.