T lymphocytes through different cytokine-mediated mechanisms" by Zhao etal from Neurobiology of Disease, 2012.
ABSTRACT
Activated microglia and infiltrating lymphocytes are neuropathological hallmarks of amyotrophic lateral sclerosis
(ALS), a fatal motoneuron disease. Although both cell types play pivotal roles in the ALS pathogenic process,
the interactions between microglia and lymphocytes, specifically regulatory CD4+CD25High T
lymphocytes (Tregs) and cytotoxic CD4+CD25− T lymphocytes (Teffs), have not been addressed. When
co-cultured with mSOD1 adult microglia, mSOD1 Tregs suppressed the cytotoxic microglial factors NOX2
and iNOS through an IL-4-mediated mechanism, whereas Teffs were only minimally effective; IL-4 inhibitory
antibodies blocked the suppressive function of mSOD1 Tregs, and conditioned media from mSOD1 Tregs or
the addition of IL-4 reduced microglial NOX2 expression. During the stable disease phase, the total number
of Tregs, specifically the numbers of CD4+CD25HighIL-4+, CD4+CD25HighIL-10+ and CD4+CD25HighTGF-β+
Tregs, were increased in ALS mice compared with WT mice; Tregs isolated during this phase reduced Teff
proliferation. In contrast, during the rapidly progressing phase, the number of mSOD1 Tregs decreased
while the proliferation of mSOD1 Teffs increased. The combination of IL-4, IL-10, and TGF-β was required
to inhibit the proliferation of mSOD1 Teffs by mSOD1 Tregs that were isolated during the slow phase,
while inhibition of mSOD1 Teffs by mSOD1 Tregs during the rapid phase, as well as WT Teffs, was not dependent
on these factors. Thus, mSOD1 Tregs at the slow phase suppressed microglial toxicity and SOD1 Teff proliferation
through different mechanisms; microglial activation was suppressed through IL-4 whereas mSOD1
Teffs were suppressed by IL-4, IL-10 and TGF-β. These data suggest that mSOD1 Tregs contribute to the slowly
progressing phase in ALS mice and may offer a novel therapeutic option for ALS patients.