Killer cell Ig-like receptor (KIR) 3DL1 down-regulation enhances inhibition of type 1 diabetes by autoantigen-specific regulatory T cells

Abstract

Both Foxp3 + regulatory T cells (Tregs) and antigen-expanded Foxp3 − Tregs play an important role in regulating immune responses as well as in preventing autoimmune diseases and graft rejection. Molecular mechanisms modulating Treg function remain largely unclear, however. We report here on the expression and function of an inhibitory killer cell Ig-like receptor, KIR3DL1, in a nonobese diabetic (NOD) mouse-derived autoantigen-specific Treg (2D2), which protects from type 1 diabetes (T1D) in adoptive transfer experiments. This gene is not expressed in T1D pathogenic T cells (Tpaths) or non-Tpath T cells. KIR genes are known to play an important role in regulating natural killer (NK) cell function, but their role in Tregs and T1D is unknown. To examine whether KIR3DL1 expression may modulate Treg function, we used shRNA to down-regulate KIR3DL1 expression (2D2-shKIR). We find that KIR3DL1 down-regulation enhances in vitro function, as measured by improved suppression of target cell proliferation. Antibody blockade of IL-10 but not IL-4 partially abrogated suppressive function. In vivo function is also improved. Adoptive transfer of 2D2-shKIR into 10-wk-old NOD mice prevented spontaneous insulitis and T1D, and the inhibitory effect was further improved if the cells were transferred earlier into 6-wk-old NOD mice. These studies indicate that KIR3DL1 expression may negatively regulate Treg function and suggest a previously undescribed target for improving immune tolerance for potential treatment of autoimmune diseases like T1D.

Leishmania donovani skews the CD56+ Natural Killer T cell response during human visceral leishmaniasis

“…Leishmania induced Tregs accumulate at the infection site and multiply in response to L. donovani [6]. Tregs are negatively regulated by KIR in type-1 diabetes [48]. KIR is inhibitory or activating, depending upon binding with its respective ligands [8,24,49].…”

Inhibition of S-phase kinase-associated protein 2 (Skp2) reprograms and converts diabetogenic T cells to Foxp3 + regulatory T cells

“…Understanding the genetic and signaling mechanisms controlling the functional determination of these T cells should help maintain immune tolerance and suppression of self-tissue destruction by Tpaths. Comparative gene array analyses have shown that autoreactive Tpaths and Tregs express a distinct gene profile (10). The genes responsible for the functional determination of Tpaths vs. Tregs remain unclear, however.…”

Pathogenic and Regulatory T Cells in Type 1 Diabetes: Losing Self-Control, Restoring It, and How to Take the Temperature

“…Another interesting set of experiments was done by Qin et al [43], who described the expression and function of the inhibitory killer cell immunoglobulinlike receptor KIR3DL1 in GAD-specific Tregs (2D2) derived from NOD mice. KIR3DL1 is a member of the KIR family, which plays an important role in regulating natural killer cell function.…”

“…Downregulation of KIR3DL1 was able to enhance the regulatory function of Tregs and their ability to inhibit insulitis and diabetes development in the NOD mouse. This receptor could be a new molecular target for the improvement of Treg functional potency and successful Treg-based cellular immunotherapy [43].…”