In CD4+ T-Cell-Induced Diabetes, Macrophages Are the Final Effector Cells that Mediate Islet β-Cell Killing

Abstract

To understand better how diabetogenic CD4 ؉ T cells induce isletType 1 diabetes mellitus (T1DM) is an autoimmune disorder wherein the pancreatic islet ␤ cells are destroyed by autoreactive T cells resulting in a state of persistent hyperglycemia. The nonobese diabetic (NOD) mouse and the bio breeding (BB) rat are two attractive animal models for T1DM that follow many characteristics of the human disease including the expression of the diabetessusceptible class II major histocompatibility complex (MHC) alleles. 1-3 T1DM in both humans and rodents is characterized by distinct histopathological stages. The first stage, termed peri-insulitis, consists of an initial infiltration of leukocytes surrounding the islets without apparent effect on ␤ cells; this is followed by an aggressive phase wherein the infiltrate actively invades the islets and kills the ␤ cells, leading to diabetes. CD4 ϩ T cells are essential for development of diabetes by recognizing ␤-cell antigens in the context of the class II MHC I-A g7 . Involvement of CD8 ϩ T cells has also been extensively documented. 4 -7 Various mechanisms for inducing ␤-cell death have been proposed including a role for Fas/FasL, perforin/granzyme pathway, Rae1-NKG2D interaction, and reactive oxygen species induced by proinflammatory cytokines. 8 -12 A major hurdle in understanding the role of various leukocytes in T1DM is the large and varied time span between peri-insulitis and onset of diabetes (in NOD mice it can be anywhere between 10 to 14 weeks). Moreover, the presence of both CD4 ϩ and CD8 ϩ T cells makes it difficult to dissect the effector pathways used by each to induce islet ␤-cell death. To this end, we have examined an accelerated model of T1DM using the diabetogenic CD4 ϩ T cell, BDC2.5, expressed as a T-cell receptor (TCR) transgene in NOD mice (from here on referred to as BDC T cells). BDC T cells recognize an unidentified islet ␤-cell antigen presented by the I-A g7 class II MHC molecule of NOD mice. 13 Activated BDC T cells transfer diabetes into NOD.scid recipients in a short period of time with reproducible kinetics and incidence.

Entry of diabetogenic T cells into islets induces changes that lead to amplification of the cellular response

“…For experiments using STZ, a dose of 50 mg/kg i.p. was administered for two consecutive days (24). PTx treatment was performed as in ref.…”

Polarization of Macrophages in Metabolic Diseases

“…ROS mediates apoptosis [49]. The importance of proinflammatory macrophages in T1D was demonstrated by clodronate depletion of macrophages in diabetogenic CD4 + T-cells in NOD mice that inhibit activation and differentiation of monocytes into effector macrophage by reducing the macrophage islet β-cell lytic capacity and prevents severe diabetes development [98]. Entry of the macrophages into the T1D islets is dependent on complement receptor 3 interactions as complement 3 antibody inhibition markedly delay disease development [99].…”

IAPP and type 1 diabetes: implications for immunity, metabolism and islet transplants

“…Given the role of macrophages and islet inflammation in initiating T1D (Oschilewski et al 1985, Charlton et al 1988, Lee et al 1988a,b, Chung et al 1997, Jun et al 1999a,b, Calderon et al 2006, it seems plausible that hIAPP aggregates, via induction of islet inflammation, could be a trigger or accelerator of autoimmunity in T1D. Amyloid has not been thoroughly investigated in T1D pancreas, and the deficiency of IAPP (along with insulin) associated with beta cell loss makes development of extensive amyloid plaques in T1D seem unlikely.…”