An immune response triggered by T-cells contributed to the elimination of motor neurons in a mouse model of amyotrophic lateral sclerosis (ALS), a study shows.
The study, “Cytotoxic CD8+ T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons,” was published in PNAS.
ALS is a progressive neurological disorder in which motor neurons — the nerve cells responsible for controlling voluntary muscles — gradually degenerate and die, causing muscles to shrink (atrophy) and become weaker.
Besides motor neurons’ destruction, ALS is also characterized by neural inflammation triggered by the accumulation of abnormal glial cells (nerve cells that support neurons), together with infiltration of immune cells.
Previous studies in mice have shown that there is infiltration of two types of immune cells — CD4-positive and CD8-positive T-cells (T-cells that contain the CD4 or CD8 receptors on their surface and are responsible for detecting and destroying pathogens) — in the brain and spinal cord.
While CD4-positive T-cells “have gained a certain interest due to their neuroprotective function in ALS,” the role of CD8-positive T-cells in ALS remains poorly understood, researchers said.
In this study, researchers from the University of Montpellier in France set out to investigate the role of CD8-positive T-cells in a mouse model of ALS.
First, they observed that CD8-positive T-cells infiltrate the central nervous system (CNS) of the animals during symptomatic (active) stages of ALS. When investigators eliminated CD8-positive T-cells from animals, the loss of motor neurons decreased significantly.
Then, to investigate the relationship between CD8-positive T-cells and motor neurons in more detail, scientists used an in vitro lab culture system composed of motor neurons and CD8-positive T-cells collected from ALS mice.
They found that the CD8-positive T-cells specifically recognized and killed motor neurons. In addition, they discovered that CD8-positive T-cells were able to identify and interact with motor neurons through the major histocompatibility complex class I (a set of molecules found on the cells’ surface that display peptides to activate T-cells and initiate an immune response, MHC-I complex).
On the other hand, activated CD8-positive T-cells produced a cytokine (a molecule that mediates and regulates immune and inflammatory response) called interferon-gamma that induced the expression of MHC-I complex molecules on the surface of motor neurons, creating a positive feedback loop of immune and inflammatory response.
Finally, after re-analyzing and comparing the features of CD8-positive T-cells from the CNS and peripheral blood of animals, investigators found that T-cells from the CNS identified and responded only to some antigens (substances seen as threats by the immune system), confirming that autoreactive (activated) CD8-positive T-cells were specifically recruited to the CNS of ALS mice.
“Together, these results suggest that an autoimmune T-cell response contributes to ALS [development]. The use of drugs with an unfocused spectrum of action (cyclophosphamide, azathioprine and prednisone) does not afford relevant insight into the selective contribution of autoimmunity in ALS,” the researchers stated.
“The inherent challenge is now to identify auto-antigens that are recognized by those [killer] T-cells and to define pertinent combinatorial therapeutic approaches embracing the complexity of the immune response in ALS,” they said.