Deficiency in B7-H1 (PD-L1)/PD-1 Coinhibition Triggers Pancreatic β-Cell Destruction by Insulin-Specific, Murine CD8 T-Cells

Abstract

OBJECTIVERIP-B7.1 mice expressing the costimulator molecule B7.1 (CD80) on pancreatic β-cells are a well established model to characterize preproinsulin-specific CD8 T-cell responses and experimental autoimmune diabetes (EAD). Different immunization strategies could prime preproinsulin-specific CD8 T-cells in wild-type C57BL/6 (B6) mice, but did not induce diabetes. We tested whether altering the B7-H1 (PD-L1) coinhibition on pancreatic β-cells can reveal a diabetogenic potential of preproinsulin-specific CD8 T-cells.RESEARCH DESIGN AND METHODSDNA-based immunization and adoptive T-cell transfers were used to characterize the induction of preproinsulin-specific CD8 T-cell responses and EAD in RIP-B7.1, B6, B7-H1−/−, PD-1−/− or bone marrow chimeric mice.RESULTSPreproinsulin-specific CD8 T-cells primed in B6 mice revealed their diabetogenic potential after adoptive transfer into congenic RIP-B7.1 hosts. Furthermore, preproinsulin-specific CD8 T-cells primed in anti-B7-H1 antibody-treated B6 mice, or primed in B7-H1−/− or PD-1−/− mice induced EAD. Immunization of bone marrow chimeric mice showed that deficiency of either B7-H.1 in pancreatic β-cells or of PD-1 in autoreactive CD8 T-cells induced EAD.CONCLUSIONSAn imbalance between costimulator (B7.1) and coinhibitor (B7-H1) signals on pancreatic β-cells can trigger pancreatic β-cell-destruction by preproinsulin-specific CD8 T-cells. Hence, regulation of the susceptibility of the β-cells for a preproinsulin-specific CD8 T-cell attack can allow or suppress EAD.

Programmed cell death 1 (PD-1) regulates the effector function of CD8 T cells via PD-L1 expressed on target keratinocytes

“…While NOD severe combined immunodeficiency (SCID) mice developed diabetes after adoptive transfer of splenocytes from NOD mice, early onset of diabetes was observed in PD-L1/L2-KO NOD SCID mice [26]. Another group also showed that PD-L1-deficiency in rat-insulin promotor (RIP)-B7.1 Tg mice accelerated to the development diabetes after immunization with preproinsulin-encoding vectors [27]. In a murine model of autoimmune myocarditis that develops in cMy-mOVA mice, PD-L1/L2-KO cMy-OVA Tg mice transferred with OT-I cells developed more severe myocarditis after immunization with OVA than do wild-type cMy-OVA Tg mice [28].…”

Immunological in vivo effects of B7-H1 deficiency

“…The lack of B7-H1 in certain cell types has been shown to have pronounced effects in several disease models, i.e., B7-H1 deficiency increases the protective potential of tolerogenic DC against experimental autoimmune encephalomyelitis (EAE) [17]. B7-H1-deficient MDSC cannot protect islet transplants as successfully as wild-type (WT) MDSC due to their strongly diminished capacity to induce Treg [29]; pancreatic ␤-cells lacking B7-H1 are more susceptible to distraction by specific CD8 T-cells in experimental autoimmune diabetes, [30] and B7-H1-deficient liver sinusoidal endothelial cells are unable to induce CD8 T-cell tolerance in the liver [31]. Another strain of B7-H1KO mice was generated in parallel by Latchman and colleagues, who demonstrated a negative regulation of T-cells in the model of EAE [32].…”

The role of co-inhibitory signals in spontaneous tolerance of weakly mismatched transplants

“…PD-L1 is expressed in many cells, including beta cells of the islets (Wang et al 2005). Lack of PD-L1/PD-1 in NOD mice (Keir et al 2006;Wang et al 2005), or in an induced diabetes model (Rajasalu et al 2010), potentiated the onset of autoimmune diabetes, which suggested that PD-L1 and PD-1 interaction has a protective role in islets. Therefore, we speculated that the absence of PD-1/PD-L1 interactions within parenchymal tissues might play a role in the rejection of male islet grafts.…”