Reversal of Autoimmunity by Boosting Memory-like Autoregulatory T Cells

Abstract

Blunting autoreactivity without compromising immunity remains an elusive goal in the treatment of autoimmunity. We show that progression to autoimmune diabetes results in the conversion of naive low-avidity autoreactive CD8(+) T cells into memory-like autoregulatory cells that can be expanded in vivo with nanoparticles coated with disease-relevant peptide-major histocompatibility complexes (pMHC-NP). Treatment of NOD mice with monospecific pMHC-NPs expanded cognate autoregulatory T cells, suppressed the recruitment of noncognate specificities, prevented disease in prediabetic mice, and restored normoglycemia in diabetic animals. pMHC-NP therapy was inconsequential in mice engineered to bear an immune system unresponsive to the corresponding epitope, owing to absence of epitope-experienced autoregulatory T cells. pMHC-NP-expanded autoregulatory T cells suppressed local presentation of autoantigens in an interferon-gamma-, indoleamine 2,3-dioxygenase-, and perforin-dependent manner. Nanoparticles coated with human diabetes-relevant pHLA complexes restored normoglycemia in a humanized model of diabetes. These observations expose a paradigm in the pathogenesis of autoimmunity amenable for therapeutic intervention.

Treg cells in pancreatic lymph nodes: the possible role in diabetogenesis and β cell regeneration in a T1D model

“…7 The finding that insulin-secreting cells could fully recover under conditions that restrain their devastation inspired exploration of the immunomodulatory approaches for therapy of T1D. [8][9][10][11][12][13][14] To further explore the concept that suppression of autoimmunity could become an adequate condition for recovery of the autologous insulin-secreting tissue, we established a model in which recovery of the physiological function of the autologous b cells was achieved in nonobese diabetic (NOD) mice by induction of allogeneic hemopoietic chimerism after the onset of hyperglycemia. The therapeutic regimen utilized in this model consisted of transplantation of allogeneic bone marrow (BM) in combination with the islets of Langerhans, which were MHC-matched to the donor's BM.…”

“…This observation supports our conclusions that: (i) the lack of the Treg cells and the impaired function of the CXCR4/SDF-1 axis in the PLNs of the NOD mice may play a role in diabetogenesis; and (ii) that an improved Treg cell accumulation in the PLNs reflects recovery of the peripheral tolerance in the PLNs of the antea-diabetic NOD mice and is part of the mechanisms leading to the resumption of euglycemia in these animals. In light of the recent finding that full regeneration of the b cells to their physiologic capacity could be achieved in the murine model of T1D after the onset of hyperglycemia, [8][9][10][11][12][13]18 immunomodulatory protocols aiming at promoting Treg cell retention in the PLNs can be considered possible means for induction of a condition favoring b cell regeneration in T1D.…”

Apportioning Blame: Autoreactive CD4+ and CD8+ T Cells in Type 1 Diabetes

“…It has also been reported that CD8 + T cells specific for peptide epitopes derived from autoantigens expressed by islet cells can be differentiated into regulatory T cells (Tsai et al 2010). Immunization of NOD mice transgenic for a TCR derived from a diabetogenic CD8 + T cell, specific for an IGRP peptide, led to the differentiation of CD8 + T cells with an autoregulatory phenotype (Tsai et al 2010).…”

“…Immunization of NOD mice transgenic for a TCR derived from a diabetogenic CD8 + T cell, specific for an IGRP peptide, led to the differentiation of CD8 + T cells with an autoregulatory phenotype (Tsai et al 2010). These memory-like autoregulatory T cells not only prevented the development of T1D in prediabetic animals, but also restored normoglycemia in diabetic animals.…”

“…The mechanism proposed by which these cells operate seems to be by deletion of antigen-presenting cells bearing the specific peptide in the cell surface in a perforin-dependent mechanism. Moreover, in a polyclonal T cell animal model expressing a human class I HLA molecule, two different nanoparticle systems bearing peptides derived from either IGRP or PPI were capable of generating memory-like autoregulatory CD8 T cells and restore normoglycemia in a high percentage of treated animals (Tsai et al 2010).…”