IL-2 protects lupus-prone mice from multiple end-organ damage by limiting CD4− CD8− IL-17–producing T cells

M Mizui, T Koga, LA Lieberman, J Beltran… - The Journal of …, 2014 - journals.aai.org
M Mizui, T Koga, LA Lieberman, J Beltran, N Yoshida, MC Johnson, R Tisch, GC Tsokos
The Journal of Immunology, 2014journals.aai.org
IL-2, a cytokine with pleiotropic effects, is critical for immune cell activation and peripheral
tolerance. Although the therapeutic potential of IL-2 has been previously suggested in
autoimmune diseases, the mechanisms whereby IL-2 mitigates autoimmunity and prevents
organ damage remain unclear. Using an inducible recombinant adeno-associated virus
vector, we investigated the effect of low systemic levels of IL-2 in lupus-prone MRL/Fas
lpr/lpr (MRL/lpr) mice. Treatment of mice after the onset of disease with IL-2-recombinant …
Abstract
IL-2, a cytokine with pleiotropic effects, is critical for immune cell activation and peripheral tolerance. Although the therapeutic potential of IL-2 has been previously suggested in autoimmune diseases, the mechanisms whereby IL-2 mitigates autoimmunity and prevents organ damage remain unclear. Using an inducible recombinant adeno-associated virus vector, we investigated the effect of low systemic levels of IL-2 in lupus-prone MRL/Fas lpr/lpr (MRL/lpr) mice. Treatment of mice after the onset of disease with IL-2-recombinant adeno-associated virus resulted in reduced mononuclear cell infiltration and pathology of various tissues, including skin, lungs, and kidneys. In parallel, we noted a significant decrease of IL-17–producing CD3+ CD4− CD8− double-negative T cells and an increase in CD4+ CD25+ Foxp3+ immunoregulatory T cells (Treg) in the periphery. We also show that IL-2 can drive double-negative (DN) T cell death through an indirect mechanism. Notably, targeted delivery of IL-2 to CD122+ cytotoxic lymphocytes effectively reduced the number of DN T cells and lymphadenopathy, whereas selective expansion of Treg by IL-2 had no effect on DN T cells. Collectively, our data suggest that administration of IL-2 to lupus-prone mice protects against end-organ damage and suppresses inflammation by dually limiting IL-17–producing DN T cells and expanding Treg.
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