In a Transgenic Model of Spontaneous Autoimmune Diabetes, Expression of a Protective Class II MHC Molecule Results in Thymic Deletion of Diabetogenic CD8+ T Cells

Morgan, David; Nugent, Courtney; Raveney, Ben J. E.; Sherman, Linda A.

doi:10.4049/jimmunol.172.2.1000

Cited by 13 publications

(13 citation statements)

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“…Some T cell clones were in fact demonstrated to show specificity to both classes of MHC molecules (41)(42)(43)(44)(45)(46)(47). When positively selected, those cells with TCRs of dual class specificity should tend to differentiate into CD4 ϩ T cells rather than CD8 ϩ T cells, as observed in the present study.…”

Section: Positive Selection In the Presence Of Both Classes Of Selectsupporting

confidence: 53%

“…However, these mechanisms, in addition to other mechanisms (25, 39), could underlie the higher proportion of CD4 ϩ T cells than CD8 ϩ T cells in normal animals of normal conditions. It is also possible that these mechanisms may contribute to explain the influence of class II MHC on the differentiation of some pathogenic CD8 ϩ T cells (42,43), as recently suggested by Logunova et al (44).…”

Section: Positive Selection In the Presence Of Both Classes Of Selectmentioning

confidence: 79%

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Cross-Positive Selection of Thymocytes Expressing a Single TCR by Multiple Major Histocompatibility Complex Molecules of Both Classes: Implications for CD4+ versus CD8+ Lineage Commitment

Eshima

Suzuki

Shinohara

2006

The Journal of Immunology

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This study has investigated the cross-reactivity upon thymic selection of thymocytes expressing transgenic TCR derived from a murine CD8+ CTL clone. The Idhigh+ cells in this transgenic mouse had been previously shown to mature through positive selection by class I MHC, Dq or Lq molecule. By investigating on various strains, we found that the transgenic TCR cross-reacts with three different MHCs, resulting in positive or negative selection. Interestingly, in the TCR-transgenic mice of H-2q background, mature Idhigh+ T cells appeared among both CD4+ and CD8+ subsets in periphery, even in the absence of RAG-2 gene. When examined on β2-microglobulin−/− background, CD4+, but not CD8+, Idhigh+ T cells developed, suggesting that maturation of CD8+ and CD4+ Idhigh+ cells was MHC class I (Dq/Lq) and class II (I-Aq) dependent, respectively. These results indicated that this TCR-transgenic mouse of H-2q background contains both classes of selecting MHC ligands for the transgenic TCR simultaneously. Further genetic analyses altering the gene dosage and combinations of selecting MHCs suggested novel asymmetric effects of class I and class II MHC on the positive selection of thymocytes. Implications of these observations in CD4+/CD8+ lineage commitment are discussed.

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Section: Positive Selection In the Presence Of Both Classes Of Selectsupporting

confidence: 53%

Section: Positive Selection In the Presence Of Both Classes Of Selectmentioning

confidence: 79%

Cross-Positive Selection of Thymocytes Expressing a Single TCR by Multiple Major Histocompatibility Complex Molecules of Both Classes: Implications for CD4+ versus CD8+ Lineage Commitment

Eshima

Suzuki

Shinohara

2006

The Journal of Immunology

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“…However, examples of recognition of two different peptides bound to two different self MHC molecules, as proposed in this study for AI4, are quite limited (54 -56). They include a recent report that negative selection of a particular CD8 ϩ T cell clonotype requires recognition of both an MHC class I and an MHC class II molecule (56). Thus, there is some precedent, albeit limited, for our finding that AI4 can respond to ␤ cell peptides bound to H-2D b as well as H-2K d self MHC molecules.…”

Section: Discussionmentioning

confidence: 91%

Requirement for Both H-2Db and H-2Kd for the Induction of Diabetes by the Promiscuous CD8+ T Cell Clonotype AI4

Takaki

Lieberman

Holl

et al. 2004

The Journal of Immunology

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The NOD mouse is a model for autoimmune type 1 diabetes in humans. CD8+ T cells are essential for the destruction of the insulin-producing pancreatic β cells characterizing this disease. AI4 is a pathogenic CD8+ T cell clone, isolated from the islets of a 5-wk-old female NOD mouse, which is capable of mediating overt diabetes in the absence of CD4+ T cell help. Recent studies using MHC-congenic NOD mice revealed marked promiscuity of the AI4 TCR, as the selection of this clonotype can be influenced by multiple MHC molecules, including some class II variants. The present work was designed, in part, to determine whether similar promiscuity also characterizes the effector function of mature AI4 CTL. Using splenocyte and bone marrow disease transfer models and in vitro islet-killing assays, we report that efficient recognition and destruction of β cells by AI4 requires the β cells to simultaneously express both H-2Db and H-2Kd class I MHC molecules. The ability of the AI4 TCR to interact with both H-2Db and H-2Kd was confirmed using recombinant peptide libraries. This approach also allowed us to define a mimotope peptide recognized by AI4 in an H-2Db-restricted manner. Using ELISPOT and mimotope/H-2Db tetramer analyses, we demonstrate for the first time that AI4 represents a readily detectable T cell population in the islet infiltrates of prediabetic NOD mice. Our identification of a ligand for AI4-like T cells will facilitate further characterization and manipulation of this pathogenic and promiscuous T cell population.

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“…This negative selection of autoreactive thymocytes is mediated by thymic bone-marrow-derived cells independently from endogenous superantigens 30 . Intrathymic deletion mediated by 'protective' MHC class II occurs in a transgenic diabetes model involving a diabetogenic TCR from a CD8 + T-cell clone 31 , and in NOD mice receiving syngeneic HSC transduced with a protective MHC class II molecule 32 . In another diabetogenic TCR transgenic model in NOD mice, however, protective MHC class II molecules expressed by F 1 mice tolerize diabetogenic CD4 + T cells, not through deletion but through generation of regulatory cell populations 33 .…”

Section: Deletion Of Alloreactive and Autoreactive T Cells In The Thymusmentioning

confidence: 99%

Treatment of severe autoimmune disease by stem-cell transplantation

Sykes

Nikolic

2005

Nature

212

148

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Transplantation of haematopoietic stem cells -cells capable of self renewing and reconstituting all types of blood cell -can treat numerous lethal diseases, including leukaemias and lymphomas. It may now be applicable for the treatment of severe autoimmune diseases, such as therapy-resistant rheumatoid arthritis and multiple sclerosis. Studies in animal models show that the transfer of haematopoietic stem cells can reverse autoimmunity, and several mechanistic pathways may explain this phenomenon. The outcome of ongoing clinical trials, as well as of studies in patients and animal models, will help to determine the role that stem-cell transplantation can play in the treatment of autoimmune diseases.In this article, we review the mechanisms by which HCT might induce tolerance to allo-and autoantigens and discuss recent advances that provide hope for better treatment of severe refractory autoimmune disease. The potential for tissue regeneration using this process is also discussed. Animal models provide the rationale for HCTSusceptibility to autoimmune diseases appears to reside in haematopoietic cells. Transplantation of bone-marrow cells from lupus-prone NZB mice into lethally irradiated non-susceptible strains induced the lupus syndrome 1 . This transfer of immune diseases with haematopoietic cells was subsequently confirmed for many autoimmune diseases, including other murine models of systemic lupus erythematosus (SLE), experimental autoimmune encephalomyelitis (EAE), adjuvant arthritis, antiphospholipid syndrome and type 1 diabetes 2 . Resistance to autoimmune diseases could also be transferred to susceptible strains by haematopoietic cells. In mice, HCT from disease-resistant allogeneic animals (allo-HCT) prevented the development of SLE, type 1 diabetes, EAE and other autoimmune diseases 3,4 .Although the prevention of autoimmunity might some day be clinically feasible, at the moment we cannot predict such diseases accurately enough to justify the use of toxic preventive treatments. Unfortunately, animal studies show that preventing the onset of autoimmunity is much easier then reversing established disease. As of 2004, for example, more than 195 methods for preventing or delaying the onset of type 1 diabetes in non-obese diabetic (NOD) mice had been identified 5 . But only a few therapeutic approaches have been effective in reversing established SLE and type 1 diabetes in mice, one of which is allo-HCT 6,7 .In animals, syngeneic HCT (that is, HCT from a genetically identical donor) can be used instead of auto-HCT. For simplicity we will refer to syngeneic HCT as auto-HCT. Although allo-HCT was reliably effective in reversing autoimmunity in animals, auto-HCT did not successfully reverse type 1 diabetes or SLE. However, varying levels of disease remission were achieved following auto-HCT in models of myasthenia gravis 8 , adjuvant arthritis 9 and EAE 10 . Allo-HCT was superior in the therapy of EAE. Auto-HCT was most successful at early dis-

show abstract

In a Transgenic Model of Spontaneous Autoimmune Diabetes, Expression of a Protective Class II MHC Molecule Results in Thymic Deletion of Diabetogenic CD8+ T Cells

Cited by 13 publications

References 61 publications

Cross-Positive Selection of Thymocytes Expressing a Single TCR by Multiple Major Histocompatibility Complex Molecules of Both Classes: Implications for CD4+ versus CD8+ Lineage Commitment

Cross-Positive Selection of Thymocytes Expressing a Single TCR by Multiple Major Histocompatibility Complex Molecules of Both Classes: Implications for CD4+ versus CD8+ Lineage Commitment

Requirement for Both H-2Db and H-2Kd for the Induction of Diabetes by the Promiscuous CD8+ T Cell Clonotype AI4

Treatment of severe autoimmune disease by stem-cell transplantation

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