Abnormalities of T cell-mediated immune activation, in the absence of active somatic immune diseases, have consistently been reported in mood disorders. Apart from being important players in the regulation of cells of the immune system, T cells are essential for normal brain development. We here report studies on the relationship between circulating levels of T helper cells and structural and functional brain imaging in depressed bipolar patients. Since the CCL20-CCR6 axis is an important entry to the brain we differentiated the various T helper cell subpopulations on the basis of their chemokine receptor expression. Methods: FACS staining was performed for Th1,Th2,Th17, Th22 and T regulatory cells on frozen leukocytes of 25 consecutively admitted inpatients affected by a major depressive episode, without psychotic features, in the course of Bipolar Disorder I and 21 healthy controls. The frequency of the T helper populations was associated with DTI and fMRI data acquired on a Philips 3.0 Tesla scanner. Tract based spatial statistic was used to obtain measures of white matter integrity (fractional anisotropy, axial, radial and mean diffusivity) from a standard DTI sequence with 35 directions. Patients were also studied for fMRI through a moral valence decision task were subjects had to decide whether morally tuned stimuli were positive or negative. Results: The percentage of circulating Th17 (CCR6(+)CXCR3(neg)CCR4(+)CCR10(neg)) cells correlated positively with higher fractional anisotropy in fiber tracts contributing to the functional integrity of the brain both in patients and healthy controls, while the frequency of circulating T regulatory (CD(+)CD25(+)FOXP3(+)) cells correlated positively with higher radial and mean diffusivity in patients. The frequency of circulating T regulatory cells also correlated to lower neuronal responses to negative versus positive morally tuned stimuli in the right dorsolateral prefrontal cortex of patients. Thl cells correlated negatively with white matter integrity in several tracts (healthy controls), while the cells showed a positive correlation to the levels of pro-inflammatory cytokines (patients). Conclusion: This study shows a new putative role for Th17 cells. Th17 cells are not only playing a role in inducing autoimmunity and auto-inflammation, but might also play a counter intuitive anabolic role in the maintenance of the functional and structural integrity of the brain. (C) 2016 Elsevier Inc. All rights reserved.