Innate cells in autoimmune diabetes in mice and man (BA7P.150)

Abstract Donor Treg engraftment following immunomodulation is lower in recent diabetic compared to prediabetic NOD mice. This may be related to altered immune compartment that cannot fully support Tregs and represents an obstacle to successful therapy. Interplay of adaptive and innate immune cells is often overlooked and role natural killer cells (NKs) have only recently been appreciated. But NK subsets remain poorly understood in mice. The current study was aimed at identifying NK functional subsets with effector and regulatory properties using NOD mouse model. We found CD335+CD122+ cells among CD45+CD3- cells in lymph nodes (LN), pancreatic LN (pLN), spleen, and blood in young female non-autoimmune B6 and diabetes-prone NOD mice. Among bulk NKs, c-Kit+ and c-Kit+CD127+ were found in LN, pLN, and spleen, but c-Kit+CD127+ cells was considerably lower in NOD mouse. Interestingly, majority of CD127+ NKs were CD25+ and IL-18R++ compared to other NKs. Blood samples of long-standing diabetic and patients at-risk for diabetes in comparison to control subjects revealed majority of human NK (hNK) are NKeff (CD56+CD16+), but ratio NKeff:NKreg (CD56++CD16-) statistically decreases with disease progression resulting in a more regulatory environment. c-Kit+ hNKs are largely found in NKreg and express IL-18R with long-standing and at-risk having highest %c-Kit+ NKreg compared to controls. The challenge is to resolve the inflammatory roles of NK cells with their regulatory roles in autoimmunity.