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Impaired migratory phenotype of CD4⁺ T cells in Parkinson's disease.

ABSTRACT: Dysfunctions in the immune system appear implicated in both disease onset and progression of Parkinson's disease (PD). Neurodegeneration observed in the brain of PD patients has been associated with neuroinflammation that is linked to alterations in peripheral adaptive immunity, where CD4⁺ T cells are key players. In the present study, we elucidated the immunological aspect of PD by employing a wide range of cellular assays, immunocytochemistry and flow cytometry to examine CD4⁺ T cells. We particularly investigated the role of CD4⁺ T cell migration in the proper functioning of the adaptive immune system. Our data reveal the altered migration potential of CD4⁺ T cells derived from PD patients, along with impaired mitochondrial positioning within the cell and reduced mitochondrial functionality. In addition, a cross-sectional study of p11 levels in CD4⁺ T cell subsets showed a differentially increased level of p11 in Th1, Th2 and Th17 populations. Taken together, these results demonstrate major impairments in the functionality of peripheral CD4⁺ T cells in PD.

SUBMITTER: Mamula D

PROVIDER: S-EPMC9741605 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Impaired migratory phenotype of CD4+ T cells in Parkinson's disease.

Mamula Dejan D Khosousi Shervin S He Yachao Y Lazarevic Vesna V Svenningsson Per P

NPJ Parkinson's disease 20221210 1

Dysfunctions in the immune system appear implicated in both disease onset and progression of Parkinson's disease (PD). Neurodegeneration observed in the brain of PD patients has been associated with neuroinflammation that is linked to alterations in peripheral adaptive immunity, where CD4+ T cells are key players. In the present study, we elucidated the immunological aspect of PD by employing a wide range of cellular assays, immunocytochemistry and flow cytometry to examine CD4+< ...[more]

PMID: 36496415

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Project description:Inflammation is a physiological state where immune cells evoke a response against detrimental insults. Finding a safe and effective treatment for inflammation associated diseases has been a challenge. In this regard, human mesenchymal stem cells (hMSC), exert immunomodulatory effects and have regenerative capacity making it a promising therapeutic option for resolution of acute and chronic inflammation. T cells play a critical role in inflammation and depending on their phenotype, they can stimulate or suppress inflammatory responses. However, the regulatory effects of hMSC on T cells and the underlying mechanisms are not fully elucidated. Most studies focused on activation, proliferation, and differentiation of T cells. Here, we further investigated memory formation and responsiveness of CD4+ T cells and their dynamics by immune-profiling and cytokine secretion analysis. Umbilical cord mesenchymal stem cells (UC-MSC) were co-cultured with either αCD3/CD28 beads, activated peripheral blood mononuclear cells (PBMC) or magnetically sorted CD4+ T cells. The mechanism of immune modulation of UC-MSC were investigated by comparing different modes of action; transwell, direct cell-cell contact, addition of UC-MSC conditioned medium or blockade of paracrine factor production by UC-MSC. We observed a differential effect of UC-MSC on CD4+ T cell activation and proliferation using PBMC or purified CD4+ T cell co-cultures. UC-MSC skewed the effector memory T cells into a central memory phenotype in both co-culture conditions. This effect on central memory formation was reversible, since UC-MSC primed central memory cells were still responsive after a second encounter with the same stimuli. The presence of both cell-cell contact and paracrine factors were necessary for the most pronounced immunomodulatory effect of UC-MSC on T cells. We found suggestive evidence for a partial role of IL-6 and TGFβ in the UC-MSC derived immunomodulatory function. Collectively, our data show that UC-MSCs clearly affect T cell activation, proliferation and maturation, depending on co-culture conditions for which both cell-cell contact and paracrine factors are needed.

Project description:BackgroundIntravenous immunoglobulin (IVIG) showed its therapeutic efficacy on Kawasaki disease (KD). However, the mechanisms by which it reduces systemic inflammation are not completely understood. Dendritic cells (DCs) and T cells play critical roles in the pathogenic processes of immune disorders. Assessing the quantity of DC subsets and T cells and identifying functional molecules present on these cells, which provide information about KD, in the peripheral blood may provide new insights into the mechanisms of immunoglobulin therapy.MethodsIn total, 54 patients with KD and 27 age-matched healthy controls (HCs) were included in this study. The number, percentage, and phenotype of DC subsets and CD4+ T cells in peripheral blood were analyzed through flow cytometry.ResultsPatients with KD exhibited fewer peripheral DC subsets and CD4+ T cells than HCs. Human leucocyte antigen-DR (HLA-DR) expression was reduced on CD1c+ myeloid DCs (CD1c+ mDCs), whereas that on plasmacytoid DCs (pDCs) did not change significantly. Both pDCs and CD1c+ mDCs displayed significantly reduced expression of co-stimulatory molecules, including CD40, CD86. pDCs and CD1c+ mDCs presented an immature or tolerant phenotype in acute stages of KD. Number of circulating pDC and CD1c+ mDC significantly inversely correlated with plasma interleukin-6 (IL-6) levels in KD patients pre-IVIG treatment. No significant differences were found concerning the DC subsets and CD4+ T cells in patients with KD with and without coronary artery lesions. Importantly, these altered quantity and phenotypes on DC subsets and CD4+ T cells were restored to a great extent post-IVIG treatment. T helper (Th) subsets including Th1 and Th2 among CD4+ T cells did not show alteration pre- and post-IVIG treatment, although the Th1-related cytokine IFN-γ level in plasma increased dramatically in patients with KD pre-IVIG treatment.ConclusionspDCs and CD1c+ mDCs presented an immature or tolerant phenotype in acute stages of KD, IVIG treatment restored the quantity and functional molecules of DCs and CD4+ T cells to distinct levels in vivo, indicating the involvement of DCs and CD4+ T cells in the inflammation in KD. The findings provide insights into the immunomodulatory actions of IVIG in KD.

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Impaired migratory phenotype of CD4⁺ T cells in Parkinson's disease.

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Impaired migratory phenotype of CD4<sup>+</sup> T cells in Parkinson's disease.

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