CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS

Abstract

Neuroinflammation, marked by gliosis and infiltrating T cells, is a prominent pathological feature in diverse models of dominantly inherited neurodegenerative diseases. Recent evidence derived from transgenic mice ubiquitously overexpressing mutant Cu 2؉ / Zn 2؉ superoxide dismutase (mSOD1), a chronic neurodegenerative model of inherited amyotrophic lateral sclerosis (ALS), indicates that glia with either a lack of or reduction in mSOD1 expression enhance motoneuron protection and slow disease progression. However, the contribution of T cells that are present at sites of motoneuron injury in mSOD1 transgenic mice is not known. Here we show that when mSOD1 mice were bred with mice lacking functional T cells or CD4؉ T cells, motoneuron disease was accelerated, accompanied by unexpected attenuated morphological markers of gliosis, increased mRNA levels for proinflammatory cytokines and NOX2, and decreased levels of trophic factors and glial glutamate transporters. Bone marrow transplants reconstituted mice with T cells, prolonged survival, suppressed cytotoxicity, and restored glial activation. These results demonstrate for the first time in a model of chronic neurodegeneration that morphological activation of microglia and astroglia does not predict glial function, and that the presence of CD4؉ T cells provides supportive neuroprotection by modulating the trophic/cytotoxic balance of glia. These glial/T-cell interactions establish a novel target for therapeutic intervention in ALS and possibly other neurodegenerative diseases.amyotrophic lateral sclerosis ͉ astrocytes ͉ bone marrow transplant ͉ microglia ͉ superoxide dismutase

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

“…Similar results are also obtained with double mutant CD4 −/− mSOD1 mice 57. Mechanistically, CD4 T‐cells appear to mediate microglial activation and their absence resulted in increased cytotoxic markers and diminished neuroprotective markers 57. Of interest, adoptive transfer of activated regulatory T‐cells or effector T‐cells from wild type mice into mSOD1 recipients leads to delayed motor symptoms and extended survival 59.…”

“…In this context, T‐cells appear particularly protective 56, 57. Importantly, hybridizing RAG2 −/− onto the mSOD1 mice, creating ALS mice without any T‐cells or B‐cells, lead to severe worsening of disease progression 57. Similar results are also obtained with double mutant CD4 −/− mSOD1 mice 57.…”

“…Importantly, hybridizing RAG2 −/− onto the mSOD1 mice, creating ALS mice without any T‐cells or B‐cells, lead to severe worsening of disease progression 57. Similar results are also obtained with double mutant CD4 −/− mSOD1 mice 57. Mechanistically, CD4 T‐cells appear to mediate microglial activation and their absence resulted in increased cytotoxic markers and diminished neuroprotective markers 57.…”

“…However, under pathological circumstances, they can infiltrate the spinal cord 55. In the mSOD1 mouse model, T‐cells infiltrate the spinal cord at a time point associated with microglial activation, highlighting the potential synergy of these cells in disease in a mouse model of ALS 56, 57, 58. In this context, T‐cells appear particularly protective 56, 57.…”

“…In the mSOD1 mouse model, T‐cells infiltrate the spinal cord at a time point associated with microglial activation, highlighting the potential synergy of these cells in disease in a mouse model of ALS 56, 57, 58. In this context, T‐cells appear particularly protective 56, 57. Importantly, hybridizing RAG2 −/− onto the mSOD1 mice, creating ALS mice without any T‐cells or B‐cells, lead to severe worsening of disease progression 57.…”