Lnk/Sh2b3 regulates initiation and severity of autoimmune insulitis and contributes to diabetes risk

The Lnk/Sh2b3 adaptor protein functions as a regulatory molecule for cytokine signaling in lymphohematopoiesis. A missense variant of the <i>LNK/SH2B3</i> gene is reportedly a risk variant common to several autoimmune diseases, including type 1 diabetes (T1D). However, roles of Lnk in T1D development remain elusive. We found that <i>Lnk</i> ^<i>-/-</i> mice showed increased susceptibility to diabetes following treatment with fairly low doses of streptozotocin, manifested by hyperglycemia and insulitis accompanied by accumulation of CD8⁺ T-cells and loss of pancreatic β cells. The high susceptibility of <i>Lnk</i> ^<i>-/-</i> mice to islet damage was abolished in crosses with <i>Rag2</i> ^<i>-/-</i> mice lacking lymphocytes or <i>MyD88</i> ^<i>-/-</i> mice carrying various defects in activation of innate immune cells. In <i>Lnk</i> ^<i>-/-</i> mice pancreata, dendritic cell (DC) fractions were altered and showed augmented expression of CD40 and IL-27. Treatment with anti-CD40L or anti-GM-CSF antibodies suppressed β cell damage and prevented diabetes. Thus, Lnk regulates T-cell priming and expansion via GM-CSF- and possibly IL-27-dependent activation of pancreatic DCs after islet damage.