NK cells promote islet allograft tolerance via a perforin-dependent mechanism

Abstract

Although major histocompatibility complex (MHC) class II-restricted CD4 T cells are well appreciated for their contribution to peripheral tolerance to tissue allografts, little is known regarding MHC class I-dependent reactivity in this process. Here we show a crucial role for host MHC class I-dependent NK cell reactivity for allograft tolerance in mice induced through either costimulation blockade using CD154-specific antibody therapy or by targeting LFA-1 (also known as CD11a). Tolerance induction absolutely required host expression of MHC class I, but was independent of CD8 T cell-dependent immunity. Rather, tolerance required innate immunity involving NK1.1(+) cells, but was independent of CD1d-restricted NKT cells. Therefore, NK cells seem to be generally required for induction of tolerance to islet allografts. Additional studies indicate that CD154-specific antibody-induced allograft tolerance is perforin dependent. Notably, NK cells that are perforin competent are sufficient to restore allograft tolerance in perforin-deficient recipients. Together, these results show an obligatory role for NK cells, through perforin, for induction of tolerance to islet allografts.

The Innate Immune System in Allograft Rejection and Tolerance

“…In addition to their role promoting solid organ rejection, NK cells also facilitate tolerance induction (81)(82)(83). In a series of well-controlled experiments, Beilke et al (81) show that tolerance induction to fully mismatched islet allografts by either costimulatory blockade with CD154 Ab or Ab blockade of CD11a required the presence of both MHC class I expression and NK cells.…”

“…In a series of well-controlled experiments, Beilke et al (81) show that tolerance induction to fully mismatched islet allografts by either costimulatory blockade with CD154 Ab or Ab blockade of CD11a required the presence of both MHC class I expression and NK cells. Furthermore, using a model of fully mismatched skin transplantation, Yu et al (83) demonstrate a novel role for NK cells in regulating T cell alloreactivity.…”

Variations of the Perforin Gene in Patients With Type 1 Diabetes

“…PRF1 variations may thus be a predisposing factor for type 1 diabetes. Perforin-mediated cytotoxicity is the main effector system in clearance of virus-infected cells but may also be involved in downregulation of the immune response due to its involvement in fratricide of effector lymphocytes and antigen-presenting cells (15)(16)(17)(18)(35)(36)(37)(38)(39). Defects of both of these functions may predispose to autoimmunity by prolonging the immune response and increasing the risk of cross-reactions between viral and self antigens by molecular mimicry.…”

Role of innate immunity in tolerance induction

“…При трансплантации мышам островков экспрессия МНС 1 и НК, как было найдено, необходимы для индукции толерантности путем либо костимуляторной блокады, либо путём лечения с помощью анти-LFA-1. В этом исследовании перфорин из НК-клеток был критическим веществом для индукции толерантности [65,170].…”