New in MS Research: Tip-Dendritic Cells Promote Inflammation

Multiple Sclerosis (MS) is a chronically progressive, neuroinflammatory autoimmune disease of the central nervous system (CNS), believed to be antigen-driven and predominantly T-cell-mediated. MS is characterized by demyelinated areas or patches of sclerosis (plaques) localized within the brain and spinal cord.

The normal physiological state of CNS is considered an anti-inflammatory environment, or “immune privileged”, which is partly due to passive-entry restriction of peripheral immune cells. During MS pathogenesis myelin-specific T-cells overcome these barriers, enter the CNS and recruit inflammatory cells that will eventually target and destroy the myelin protein, which leads to axonal damage.

Cytotoxic T-cells,Multiple Sclerosis,CD4 T-Cells

Although the initial trigger leading to the development of myelin-specific T-cells in MS is still not clear, it has been shown that MS patients’ blood and cerebrospinal fluid (CSF), contain activated myelin‐reactive CD4+ T-cells, whereas only non-activated myelin‐reactive T-cells are present in non-MS samples. 

Both CD4+ and CD8+ T cells have been observed in MS acute and chronic lesions, respectively. Nonetheless, these two T-lymphocytes are activated by different CNS-resident antigen‐presenting cells (APCs) that trigger the recruitment of innate immune cells through presenting myelin antigens to CD4+ and CD8+ T cells, leading to the subsequent “determinant spreading”.

Previous studies have identified cells that present myelin to CD4+ T-cells: once inside the CNS, the CD4 molecule of autoreactive CD4+ T-cells binds to a non-polymorphic site on the major histocompatibility complex (MHC) class II, which is expressed by local myelin-presenting dendritic cells (DCs). In the absence of inflammation in CNS, there is a very low constitutive expression of MHC molecules, which are often present on cells of the lymphoid system.

In contrast CD8 molecule of the CD8+ T-cells binds to the MHC class I molecule, which serves to present specific antigens to the T-lymphocytes’s T-cell receptor (TCR). Thus, CD8+ T-cells (aka. cytotoxic T-cells) are involved in class I‐restricted lysis of antigen‐specific targets. However, until recently the APCs responsible for activating myelin-specific CD8+ T-cells were not known.

In January 2013, Goverman’s group from University of Washington showed that during experimental autoimmune encephalomyelitis (EAE)-an animal model of MS initiated by CD4+ T-cell- Tip-dendritic cells (Tip-DCs) play a major role in activating naive CD8+ T-cells. Based on this study, CD8+ T-cells are presented with MHC class I–restricted myelin basic protein (MBP) and activated by CD11b+ Tip-DCs. In addition, it was reported that under the inflammatory conditions of EAE, oligodendrocytes also presented MBP, to the CD8+ T-cells, which made them recognizable targets of the activated myelin-specific CD8+ T-cells, leading to sustained chronic inflammation (aka. Determinant spreading). This suggests that myelin-specific CD8+ T-cells may be responsible for the ongoing axonal destruction in “slow burning” MS lesions by directly lysing oligodendrocytes.

Tip-Dendritic Cells,CD8+ T-cells,Multiple Sclerosis

Tip-DCs are likely derived from the inflammatory monocytes that have accumulated in the brain and the spinal cord during EAE. Goverman proposed that one possible mechanism of acquiring MBP by Tip-DCs is via phagocytosing and processing myelin debris or dead oligodendrocytes, and then presenting the myelin peptides. Furthermore, they also hypothesized that CD8+ T-cells activated by Tip-DCs may contribute to the immune cascade amplification by secreting additional Interferon-gamma (IFN-γ) within CNS.

 

Identifying specific DCs involved in antigen-presenting and activation of all T-lymphocytes involved in the neuroinflammatory response is important for the development of potential autoimmune disease therapies that target immunogenic DC functions. Although Goverman’s findings may seem marginal on the surface, it is in fact a big step forward in understanding the etiology of MS; further investigations are required to address the origin of these Tip-DCs and the precise mechanisms through which they become myelin-presenting cells. Also, future studies in human MS are essential to confirm Tip-DCs’ reported functions as well as their interactions with patients’ oligodendrocytes.

Further reading:

MHC class I-restricted myelin epitopes are cross-presented by Tip-DCs that promote determinant spreading to CD8(+) T cells.

Antigen Presentation in the CNS by myeloid dendritic cells drives progression of relapsing experimental autoimmune encephalomyelitis. 

Dendritic cell CNS recruitment correlates with disease severity in EAE via CCL2 chemotaxis at the blood–brain barrier through paracellular transmigration and ERK activation.

 

About Nousha Khosh

Nousha Khosh, MS is currently a research scientist at the City of Hope-Beckman Research Institute and is also an MBA candidate at the Paul Merage School of Business at UC Irvine. Her research emphasis is on the optical analysis utilization of Neural Progenitor Cells in glioma therapy as well as mechanisms involved in the Epithelial-Mesenchymal-Transition of brain tumors