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Introduction: We reported that Ca2+-independent phospholipase A2β (iPLA2β)-derived lipids (iDLs) contribute to type 1 diabetes (T1D) onset. As CD4+ and CD8+ T cells are critical in promoting p-cell death, we tested the hypothesis that iDL signaling from these cells participates in T1D development. Methods: CD4+ and CD8+ T cells from wild-type non-obese diabetic (NOD) and NOD.iPLA2β+/- (NOD.HET) mice were administered in different combinations to immunodeficient NOD.scid. Results: In mice receiving only NOD T cells, T1D onset was rapid (5 weeks), incidence 100% by 20 weeks, and islets absent. In contrast, onset was delayed 1 week and incidence reduced 40%-50% in mice receiving combinations that included NOD.HET T cells. Consistently, islets from these non-diabetic mice were devoid of infiltrate and contained insulin-positive β-cells. Reduced iPLA2p led to decreased production of proinflammatory lipids from CD4+ T cells including prostaglandins and dihydroxyeicosatrienoic acids (DHETs), products of soluble epoxide hydrolase (sEH), and inhibition of their signaling decreased (by 82%) IFNγ+CD4+ cells abundance. However, only DHETs production was reduced from CD8+ T cells and was accompanied by decreases in sEH and granzyme B. Discussion: These findings suggest that differential select iDL signaling in CD4+ and CD8+ T cells contributes to T1D development, and that therapeutics targeting such signaling might be considered to counter T1D. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is characterized by T‐cell responses to islet antigens. Investigations in humans and the nonobese diabetic (NOD) mouse model of T1D have revealed that T‐cell reactivity to insulin plays a central role in the autoimmune response. As there is no convenient NOD‐based model to study human insulin (hIns) or its T‐cell epitopes in the context of spontaneous T1D, we developed a NOD mouse strain transgenically expressing hIns in islets under the control of the human regulatory region. Female NOD.hIns mice developed T1D at approximately the same rate and overall incidence as NOD mice. Islet‐infiltrating T cells from NOD.hIns mice recognized hIns peptides; both CD8 and CD4 T‐cell epitopes were identified. We also demonstrate that islet‐infiltrating T cells from HLA‐transgenic NOD.hIns mice can be used to identify potentially patient‐relevant hIns T‐cell epitopes. Besides serving as an antigen, hIns was expressed in the thymus of NOD.hIns mice and could serve as a protector against T1D under certain circumstances, as previously suggested by genetic studies in humans. NOD.hIns mice and related strains facilitate human‐relevant epitope discovery efforts and the investigation of fundamental questions that cannot be readily addressed in humans. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is an autoimmune disease resulting from defects in central and peripheral tolerance and characterized by T cell-mediated destruction of islet [beta] cells. Cytotoxic [CD8.sup.+] T cells, reactive to [beta] cell antigens, are required for T1D development in the NOD mouse model of the disease, and [CD8.sup.+] T cells specific for [beta] cell antigens can be detected in the peripheral blood of T1D patients. It has been evident that in nonautoimmune-prone mice, dendritic cells (DCs) present model antigens in a tolerogenic manner in the steady state, e.g., in the absence of infection, and cause T cells to proliferate initially but then to be deleted or rendered unresponsive. However, this fundamental concept has not been evaluated in the setting of a spontaneous autoimmune disease. To do so, we delivered a mimotope peptide, recognized by the diabetogenic [CD8.sup.+] T cell clone AI4, to DCs in NOD mice via the endocytic receptor DEC-205. Proliferation of transferred antigen-specific T cells was initially observed, but this was followed by deletion. Tolerance was achieved because rechallenge of mice with the mimotope peptide in adjuvant did not induce an immune response. Thus, targeting of DCs with [beta] cell antigens leads to deletion of autoreactive [CD8.sup.+] T cells even in the context of ongoing autoimmunity in NOD mice with known tolerance defects. Our results provide support for the development of DC targeting of self antigens for treatment of chronic T cell-mediated autoimmune diseases. autoimmune disease | type 1 diabetes

Type 1 diabetes is an autoimmune disease in which autoreactive T cells attack and destroy the insulin-producing pancreatic [beta] cells. [CD8.sup.+] T cells are essential for this [beta] cell destruction, yet their specific antigenic targets are largely unknown. Here, we reveal that the autoantigen targeted by a prevalent population of pathogenic [CD8.sup.+] T cells in nonobese diabetic mice is islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP). Through tetramer technology, IGRP-reactive T cells are readily detected in islets and peripheral blood directly ex vivo. The human IGRP gene maps to a diabetes susceptibility locus, suggesting that IGRP also may be an antigen for pathogenic T cells in human type I diabetes and, thus, a new, potential target for diagnostic and therapeutic approaches.

Nonobese diabetic (NOD) mice develop insulin-dependent diabetes mellitus due to autoimmune T lymphocyte-mediated destruction of pancreatic [Beta] cells. Although both major histocompatibility complex class I-restricted [CD8.sup.+] and class II-restricted [CD4.sup.+] T cell subsets are required, the specific role each subset plays in the pathogenic process is still unclear. Here we show that class I-dependent T cells are required for all but the terminal stages of autoimmune diabetes development. To characterize the diabetogenic [CD8.sup.+] T cells responsible, we isolated and propagated in vitro [CD8.sup.+] T cells from the earliest insulitic lesions of NOD mice. They were cytotoxic to NOD islet cells, restricted to H-[2K.sup.d], and showed a diverse T cell receptor [Beta] chain repertoire. In contrast, their [Alpha] chain repertoire was more restricted, with a recurrent amino acid sequence motif in the complementarity-determining region 3 loop and a prevalence of V[Alpha]17 family members frequently joined to the J[Alpha]42 gene segment. These results suggest that a number of the [CD8.sup.+] T cells participating in the initial phase of autoimmune [Beta] cell destruction recognize a common structural component of [K.sup.d]/peptide complexes on pancreatic [Beta] cells, possibly a single peptide.

The specificity of T cell-mediated immune responses is primarily determined by the interaction between the T cell receptor (TCR) and the antigenic peptide presented by the major histocompatibility complex (MHC) molecules. To refine our understanding of interactions between the TCR and the antigenic peptide of vesicular stomatitis virus (VSV) presented by the class I MHC molecule H-2[K.sup.b], we constructed a TCR [Alpha] chain transgenic mouse in a TCR [Alpha]-deficient background to define specific structural features in the TCR [Beta] chain that are important for the recognition of the VSV/H.2[K.sup.b] complex. We found that for a given peptide, a peptide-specific, highly conserved amino acid could always be identified at position 98 of the complementarity-determining region 3 (CDR3) loop of TCR [Beta] chains. Further, we demonstrated that substitutions at position 6, but not position 1, of the VSV peptide induced compensatory changes in the TCR in both the amino acid residue at position 98 and the length of the CDR3[Beta] loop. We conclude that the amino acid residue at position 98 of the CDR3[Beta] loop is a key residue that plays a critical role in determining the specificity of TCR-VSV/H-2[K.sup.b] interactions and that a specific length of the CDR3[Beta] loop is required to facilitate such interactions. Further, these findings suggest that the [Alpha] and [Beta] chains of TCRs interact with amino acid residue(s) toward the N and C termini of the VSV peptide, respectively, providing functional evidence for the orientation of a TCR with its peptide/MHC ligand as observed in the crystal structures of TCR/peptide/MHC complexes.