The Microbial Product Lipopolysaccharide Confers Diabetogenic Potential on the T Cell Repertoire of BDC2.5/NOD Mice: Implications for the Etiology of Autoimmune Diabetes

Lee

The Journal of Immunology

et al. 2011

We have reported that apoptotic β cells undergoing secondary necrosis, called “late apoptotic (LA) β cells,” stimulated APCs and induced diabetogenic T cell priming through TLR2, which might be one of the initial events in autoimmune diabetes. Indeed, diabetogenic T cell priming and the development of autoimmune diabetes were significantly inhibited in TLR2-null NOD mice, suggesting the possibility that TLR2 blockade could be used to inhibit autoimmune diabetes. Because prolonged TLR stimulation can induce TLR tolerance, we investigated whether repeated TLR2 administration affects responses to LA β cells and inhibits autoimmune diabetes in NOD mice by inducing TLR2 tolerance. Treatment of primary peritoneal macrophages with a TLR2 agonist, Pam3CSK4, suppressed cytokine release in response to LA insulinoma cells or further TLR2 stimulation. The expression of signal transducer IRAK-1 and -4 proteins was decreased by repeated TLR2 stimulation, whereas expression of IRAK-M, an inhibitory signal transducer, was enhanced. Chronic Pam3CSK4 administration inhibited the development of diabetes in NOD mice. Diabetogenic T cell priming by dendritic cells and upregulation of costimulatory molecules on dendritic cells by in vitro stimulation were attenuated by Pam3CSK4 administration in vivo. Pam3CSK4 inhibited diabetes after adoptive transfer of diabetogenic T cells or recurrence of diabetes after islet transplantation by pre-existing sensitized T cells. These results showed that TLR2 tolerance can be achieved by prolonged treatment with TLR2 agonists, which could inhibit priming of naive T cells, as well as the activity of sensitized T cells. TLR2 modulation could be used as a novel therapeutic modality against autoimmune diabetes.

Section: Discussionmentioning

confidence: 99%

Inhibition of Autoimmune Diabetes by TLR2 Tolerance

Lee

The Journal of Immunology

et al. 2011

“…Injecting LPS into mice in which the T cell repertoires are restricted to either islet Ag or myelin basic protein (MBP) results in autoimmune diabetes or experimental autoimmune encephalomyelitis (EAE), respectively. 45,46 The latter study found that inducing EAE in mice with a normal T cell repertoire renders them susceptible to relapse following a future LPS injection, indicating that Ag-experienced T cells may be preferentially targeted by LPS. This effect is not restricted to self-specific T cells, as infecting C57BL/6 mice with Salmonella typhimurium causes CD4 T cells to respond to a subsequent LPS injection by producing the effector cytokine IFN-γ.…”

Section: A Historical View Of the Lps-t Cell Adjuvant Effectmentioning

confidence: 94%

Understanding How Lipopolysaccharide Impacts CD4 T-Cell Immunity

2008

Lipopolysaccharide (LPS) is a natural adjuvant synthesized by gram-negative bacteria that has profound effects on CD4 T cell responses. LPS stimulates cells through Toll-like receptor 4 (TLR4), causing the release of inflammatory cytokines and upregulation of costimulatory molecules on antigen presenting cells. The combination of signals from antigen, costimulation, and cytokines allow CD4 T cells to overcome suppressive barriers and accumulate in large numbers. T cells that are primed in an LPS-stimulated environment are programmed for long-term survival following clonal expansion. LPS is well-known for generating Th1 responses, however, under appropriate conditions it can also support differentiation into other T helper lineages, demonstrating its pleiotropic nature. Although molecular analyses have provided insights into how immune responses are controlled by LPS in vivo, its powerful adjuvant activity is also associated with toxicity. Research on partial TLR4 agonists such as monophosphoryl lipid A have demonstrated that toxicity and immunogenicity are not always linked, making them useful candidates for human vaccines. In this sense, many years of LPS research have ultimately contributed to vaccine design, and the next generation may involve studying how the balance between different CD4 T cell subsets is controlled.

“…Infiltration of the pancreatic islets is precocious and synchronized (18). It seems, in this transgenic mouse, that the regulatory genes (36), molecules (37), cells (36), or intercellular milieu (38,39) that modulate the progression to diabetes all act at a peripheral level, affecting the damage wrought there by the BDC-2.5 T cells, rather than the thymic control of their maturation.…”

Section: Introductionmentioning

confidence: 94%

Susceptible MHC alleles, not background genes, select an autoimmune T cell reactivity

Stratmann¹,

Martín‐Orozco²,

Mallet-Designe³

et al. 2003

J. Clin. Invest.

To detect and characterize autoreactive T cells in diabetes-prone NOD mice, we have developed a multimeric MHC reagent with high affinity for the BDC-2.5 T cell receptor, which is reactive against a pancreatic autoantigen. A distinct population of T cells is detected in NOD mice that recognizes the same MHC/peptide target. These T cells are positively selected in the thymus at a surprisingly high frequency and exported to the periphery. They are activated specifically in the pancreatic LNs, demonstrating an autoimmune specificity that recapitulates that of the BDC-2.5 cell. These phenomena are also observed in mouse lines that share with NOD the H-2 g7 MHC haplotype but carry diabetes-resistance background genes. Thus, a susceptible haplotype at the MHC seems to be the only element required for the selection and emergence of autoreactive T cells, without requiring other diabetogenic loci from the NOD genome.