Most tissues are populated by tissue-resident memory T cells (T_RM cells), which are adapted to their niche and appear to be indispensable for local protection against pathogens. Here we show that human white matter-derived brain CD8⁺ T cells can be subsetted into CD103⁻CD69⁺ and CD103⁺CD69⁺ T cells both with a phenotypic and transcription factor profile consistent with T_RM cells. Specifically, CD103 expression in brain CD8⁺ T cells correlates with reduced expression of differentiation markers, increased expression of tissue-homing chemokine receptors, intermediate and low expression of the transcription factors T-bet and eomes, increased expression of PD-1 and CTLA-4, and low expression of cytolytic enzymes with preserved polyfunctionality upon activation. Brain CD4⁺ T cells also display T_RM cell-associated markers but have low CD103 expression. We conclude that the human brain is surveilled by T_RM cells, providing protection against neurotropic virus reactivation, whilst being under tight control of key immune checkpoint molecules.

Historically, multiple sclerosis (MS) has been viewed as being primarily driven by T cells. However, the effective use of anti-CD20 treatment now also reveals an important role for B cells in MS patients. The results from this treatment put forward T-cell activation rather than antibody production by B cells as a driving force behind MS. The main question of how their interaction provokes both B and T cells to infiltrate the CNS and cause local pathology remains to be answered. In this review, we highlight key pathogenic events involving B and T cells that most likely contribute to the pathogenesis of MS. These include (1) peripheral escape of B cells from T cell-mediated control, (2) interaction of pathogenic B and T cells in secondary lymph nodes, and (3) reactivation of B and T cells accumulating in the CNS. We will focus on the functional programs of CNS-infiltrating lymphocyte subsets in MS patients and discuss how these are defined by mechanisms such as antigen presentation, co-stimulation and cytokine production in the periphery. Furthermore, the potential impact of genetic variants and viral triggers on candidate subsets will be debated in the context of MS.

Background Multiple Sclerosis is associated with low serum levels of 25-hydroxyvitamin D (25(OH)D). We investigated the association between serum levels of 25(OH)D and 1,25-dihydroxyvitamin D (1,25(OH)2D), the biologically active metabolite, and clinical MS severity as expressed by EDSS-score and relapse rate. Study-design Cross-sectional study. Patients and Methods Serum samples from 267 MS patients were collected for 25(OH)D and 1,25(OH)2D measurement. Clinical MS parameters at the date of serum sampling were determined. Results: Both metabolite levels were significantly lower in the progressive forms compared to the relapsing remitting (RR)MS phenotype. In RRMS patients (disease course ≤ 5 years), high 25(OH)D levels were associated with a high chance of remaining relapse-free. Low 25(OH)D levels were associated with high EDSS-scores. 1,25(OH)2D was not directly associated with relapse rate or EDSS-score, and was dependent of age and 25(OH)D level. Conclusion Serum levels of 25(OH)D were associated with both relapse rate and disability in MS patients. These results are suggestive for a disease modulating effect of the serum concentrations of 25(OH)D on MS. The low circulating 1,25(OH)2D levels in progressive MS are due to older age and lower 25(OH)D levels. The potential consequences for vitamin D supplementation in MS will be discussed.

In several autoimmune diseases, including multiple sclerosis (MS), a compromised regulatory T cell (Treg) function is believed to be critically involved in the disease process. In vitro, the biologically active metabolite of vitamin D has been shown to promote Treg development. A poor vitamin D status has been linked with MS incidence and MS disease activity. In the present study, we assess a potential in vivo correlation between vitamin D status and Treg function in relapsing remitting MS (RRMS) patients. Serum levels of 25-hydroxyvitamin D (25(OH)D) were measured in 29 RRMS patients. The number of circulating Tregs was assessed by flow-cytometry, and their functionality was tested in vitro in a CFSE-based proliferation suppression assay. Additionally, the intracellular cytokine profile of T helper cells was determined directly ex-vivo by flow-cytometry. Serum levels of 25(OH)D correlated positively with the ability of Tregs to suppress T cell proliferation (R = 0.590, P = 0.002). No correlation between 25(OH)D levels and the number of Tregs was found. The IFN-γ/IL-4 ratio (Th1/Th2-balance) was more directed towards IL-4 in patients with favourable 25(OH)D levels (R = −0.435, P = 0.023). These results show an association of high 25(OH)D levels with an improved Treg function, and with skewing of the Th1/Th2 balance towards Th2. These findings suggest that vitamin D is an important promoter of T cell regulation in vivo in MS patients. It is tempting to speculate that our results may not only hold for MS, but also for other autoimmune diseases. Future intervention studies will show whether modulation of vitamin D status results in modulation of the T cell response and subsequent amelioration of disease activity.