MICRORNA CONTROL OF INFLAMMATORY AND REGULATORY T CELLS IN CENTRAL NERVOUS SYSTEM AUTOIMMUNITY - Project Summary/Abstract
An appropriate balance between inflammatory and regulatory T cells is critical to maintaining immune
homeostasis and preventing autoimmune diseases, including multiple sclerosis (MS) and its animal model,
EAE. Although the differentiation and pathogenicity of T helper subsets is known to be regulated by specific
transcription factors and cytokines, the role of microRNAs that control the balance of these cells is not well
understood. We recently uncovered an important role for the microRNA, Mir-21 in promoting inflammatory
Th17/Th1 cells and inhibiting regulatory Tr35 cells in both mice and humans. Our preliminary data suggest that
Mir-21 mediates tissue inflammation in EAE via these cell types. Specifically, we found that in Th17 cells, Mir-
21 targets Foxo1, relieves IL-23R and IL-1R from Foxo1-mediated inhibition, enhances responsiveness to IL-
23 and IL-1β, and promotes Th17 pathogenicity. Mir-21 also promotes GM-CSF expression within
differentiated Th1 cells by targeting the Foxo1-IL-1R axis. Loss of Mir-21 interferes with the expression of the
Th17/Th1 effector cytokine GM-CSF in vivo and confers striking EAE resistance. In addition, our preliminary
data show that Mir-21 may promote autoimmunity by preventing the development of regulatory Tr35 cells by
targeting IL-12p35, a subunit shared by the cytokine IL-35. Analogous to our findings in mice, we have found
that Mir-21 promotes Th17 differentiation, while inhibiting Tr35 cells, in humans. Interestingly, we have also
found increased expression of Mir-21 in T cells and other Th1/Th17 cytokines in MS patients, and that IFN-β, a
first-line therapy for MS, inhibits Mir-21 in T cells. Most importantly, we found that CD4+ T cells from IFN-β
responders expressed lower levels of Mir-21, and that non-responders had indistinguishable levels from
untreated patients. However, the exact role of Mir-21 in the regulation of Th17/Th1 and Tr35 cells in EAE and
humans, specifically MS patients, is not known. In this proposal, we will investigate how Mir-21 regulates the
balance of inflammatory and anti-inflammatory T cells in EAE and MS. In Aim 1, we will investigate the
molecular mechanisms by which Mir-21 promotes the pathogenic functions of Th17/Th1 and inhibition of
regulatory Tr35 cells in EAE. In Aim 2, we will molecularly define the mechanisms by which Mir-21 mediates
promotion of Th17 cells and inhibition of regulatory Tr35 cells, and modulates other T helper subsets in
humans. Given that our preliminary data in human T helper cells and MS patients is analogous to murine cells
and EAE mice, it is possible that the same critical pathogenic Mir-21-mediated pathways modulating EAE may
also be involved in the MS pathogenesis. Therefore, in Aim 3, we will investigate whether Mir-21 pathways
influence the balance of inflammatory Th17/Th1 and regulatory T cells in MS patients and whether regulation
by these pathways is altered in response to therapy. A better understanding of these pathways will have
important implications for navigating immune mechanisms in MS and how they relate to therapeutic efficacy.
