Tim‐1 stimulation of dendritic cells regulates the balance between effector and regulatory T cells

S Xiao, B Zhu, H Jin, C Zhu, DT Umetsu… - European journal of …, 2011 - Wiley Online Library
S Xiao, B Zhu, H Jin, C Zhu, DT Umetsu, RH DeKruyff, VK Kuchroo
European journal of immunology, 2011Wiley Online Library
We show that the T‐cell immunoglobalin mucin, Tim‐1, initially reported to be expressed on
CD4+ T cells, is constitutively expressed on dendritic cells (DCs) and that its expression
further increases after DC maturation. Tim‐1 signaling into DCs upregulates costimulatory
molecule expression and proinflammatory cytokine production, thereby promoting effector T‐
cell responses, while inhibiting Foxp3+ Treg responses. By contrast, Tim‐1 signaling in T
cells only regulates Th2 responses. Using a high‐avidity/agonistic anti‐Tim‐1 antibody as a …
Abstract
We show that the T‐cell immunoglobalin mucin, Tim‐1, initially reported to be expressed on CD4+ T cells, is constitutively expressed on dendritic cells (DCs) and that its expression further increases after DC maturation. Tim‐1 signaling into DCs upregulates costimulatory molecule expression and proinflammatory cytokine production, thereby promoting effector T‐cell responses, while inhibiting Foxp3+ Treg responses. By contrast, Tim‐1 signaling in T cells only regulates Th2 responses. Using a high‐avidity/agonistic anti‐Tim‐1 antibody as a co‐adjuvant enhances the immunogenic function of DCs, decreases the suppressive function of Tregs, and substantially increases proinflammatory Th17 responses in vivo. The treatment with high‐ but not low‐avidity anti‐Tim‐1 not only worsens experimental autoimmune encephalomyelitis (EAE) in susceptible mice but also breaks tolerance and induces EAE in a genetically resistant strain of mice. These findings indicate that Tim‐1 has an important role in regulating DC function and thus shifts the balance between effector and regulatory T cells towards an enhanced immune response. By understanding the mechanisms by which Tim‐1 regulates DC and T‐cell responses, we may clarify the potential utility of Tim‐1 as a target of therapy against autoimmunity, cancer, and infectious diseases.
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