CD4+ T Cells from Glutamic Acid Decarboxylase (GAD)65-specific T Cell Receptor Transgenic Mice Are Not Diabetogenic and Can Delay Diabetes Transfer

Glutamic acid decarboxylase (GAD)65 is an early and important antigen in both human diabetes mellitus and the nonobese diabetic (NOD) mouse. However, the exact role of GAD65-specific T cells in diabetes pathogenesis is unclear. T cell responses to GAD65 occur early in diabetes pathogenesis, yet only one GAD65-specific T cell clone of many identified can transfer diabetes. We have generated transgenic mice on the NOD background expressing a T cell receptor (TCR)-specific for peptide epitope 286–300 (p286) of GAD65. These mice have GAD65-specific CD4+ T cells, as shown by staining with an I-Ag7(p286) tetramer reagent. Lymphocytes from these TCR transgenic mice proliferate and make interferon γ, interleukin (IL)-2, tumor necrosis factor (TNF)-α, and IL-10 when stimulated in vitro with GAD65 peptide 286–300, yet these TCR transgenic animals do not spontaneously develop diabetes, and insulitis is virtually undetectable. Furthermore, in vitro activated CD4 T cells from GAD 286 TCR transgenic mice express higher levels of CTL-associated antigen (CTLA)-4 than nontransgenic littermates. CD4+ T cells, or p286-tetramer+CD4+ Tcells, from GAD65 286–300-specific TCR transgenic mice delay diabetes induced in NOD.scid mice by diabetic NOD spleen cells. This data suggests that GAD65 peptide 286–300-specific T cells have disease protective capacity and are not pathogenic.

Download Full-text

BDC12-4.1 T-Cell Receptor Transgenic Insulin-Specific CD4 T Cells Are Resistant to In Vitro Differentiation into Functional Foxp3+ T Regulatory Cells

PLoS ONE ◽

10.1371/journal.pone.0112242 ◽

2014 ◽

Vol 9 (11) ◽

pp. e112242 ◽

Cited By ~ 2

Author(s):

Ghanashyam Sarikonda ◽

Georgia Fousteri ◽

Sowbarnika Sachithanantham ◽

Jacqueline F. Miller ◽

Amy Dave ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cd4 T Cells ◽

T Regulatory Cells ◽

Cell Receptor ◽

Regulatory Cells ◽

In Vitro Differentiation

Download Full-text

A novel myelin P0–specific T cell receptor transgenic mouse develops a fulminant autoimmune peripheral neuropathy

Journal of Experimental Medicine ◽

10.1084/jem.20082113 ◽

2009 ◽

Vol 206 (3) ◽

pp. 507-514 ◽

Cited By ~ 31

Author(s):

Cédric Louvet ◽

Beniwende G. Kabre ◽

Dan W. Davini ◽

Nicolas Martinier ◽

Maureen A. Su ◽

...

Keyword(s):

T Cells ◽

Peripheral Neuropathy ◽

T Cell ◽

T Cell Receptor ◽

Cd4 T Cells ◽

Chronic Inflammatory Demyelinating Polyneuropathy ◽

Gene Knockout ◽

Premature Death ◽

Cell Receptor

Autoimmune-prone nonobese diabetic mice deficient for B7-2 spontaneously develop an autoimmune peripheral neuropathy mediated by inflammatory CD4+ T cells that is reminiscent of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. To determine the etiology of this disease, CD4+ T cell hybridomas were generated from inflamed tissue–derived CD4+ T cells. A majority of T cell hybridomas were specific for myelin protein 0 (P0), which was the principal target of autoantibody responses targeting nerve proteins. To determine whether P0-specific T cell responses were sufficient to mediate disease, we generated a novel myelin P0–specific T cell receptor transgenic (POT) mouse. POT T cells were not tolerized or deleted during thymic development and proliferated in response to P0 in vitro. Importantly, when bred onto a recombination activating gene knockout background, POT mice developed a fulminant form of peripheral neuropathy that affected all mice by weaning age and led to their premature death by 3–5 wk of age. This abrupt disease was associated with the production of interferon γ by P0-specific T cells and a lack of CD4+ Foxp3+ regulatory T cells. Collectively, our data suggest that myelin P0 is a major autoantigen in autoimmune peripheral neuropathy.

Download Full-text

Age-related changes in CD4 T cells of T cell receptor transgenic mice

Mechanisms of Ageing and Development ◽

10.1016/s0047-6374(96)01826-x ◽

1997 ◽

Vol 93 (1-3) ◽

pp. 95-105 ◽

Cited By ~ 26

Author(s):

Laura Haynes ◽

Phyllis-Jean Linton ◽

Susan L Swain

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

T Cell Receptor ◽

Cd4 T Cells ◽

Cell Receptor ◽

Age Related ◽

Age Related Changes

Download Full-text

The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice.

Journal of Experimental Medicine ◽

10.1084/jem.176.4.1091 ◽

1992 ◽

Vol 176 (4) ◽

pp. 1091-1098 ◽

Cited By ~ 671

Author(s):

R A Seder ◽

W E Paul ◽

M M Davis ◽

B Fazekas de St Groth

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

T Cell Receptor ◽

Cd4 T Cells ◽

Cell Receptor ◽

Inhibitory Effect ◽

Interleukin 4 ◽

Ifn Gamma

To study the factors that determine whether CD4+ T cells produce interleukin 4 (IL-4) or interferon gamma (IFN-gamma) upon stimulation we used a system allowing naive T cells to be primed in vitro by specific antigen. Dense CD4+ T cells were purified from mice that expressed transgenes encoding a T cell receptor specific for pigeon cytochrome C peptide 88-104 in association with I-Ek. These T cells produced very limited amounts of IL-4 and IFN-gamma upon immediate challenge with 88-104 and antigen-presenting cells (APC). However, after an initial "priming" culture in which they were incubated for 4 d in the presence of 88-104, APC, and 1,000 U/ml IL-4, the T cells acquired the capacity to produce substantial amounts of IL-4 upon rechallenge but made very little IFN-gamma. Cells primed in the absence of IL-4 produced IFN-gamma upon rechallenge but virtually no IL-4. The inhibitory effect of IL-4 on IFN-gamma production did not appear to be mediated by the induction of IL-10 production since IL-10 addition to initial cultures did not suppress priming for IFN-gamma production, nor did anti-IL-10 block the inhibitory effect of IL-4. IFN-gamma itself did not increase priming for IFN-gamma production, nor did anti-IFN-gamma reduce such priming. IFN-gamma did, however, diminish priming for IL-4 production when limiting amounts of IL-4 (100 U/ml) were used in the initial culture. The dominant effect of IL-4 in determining the lymphokine-producing phenotype of primed cells was observed with dendritic cells (DC), activated B cells, and I-Ek-transfected fibroblasts as APC. However, the different APC did vary in their potency, with DC being superior to activated B cells, which were superior to transfected fibroblasts.

Download Full-text

Antigen Feeding Increases Frequency and Antigen-specific Proliferation Ability of Intraepithelial CD4+T Cells in αβ T Cell Receptor Transgenic Mice

Bioscience Biotechnology and Biochemistry ◽

10.1271/bbb.67.1223 ◽

2003 ◽

Vol 67 (6) ◽

pp. 1223-1229 ◽

Cited By ~ 1

Author(s):

Masao GOTO ◽

Satoshi HACHIMURA ◽

Akio AMETANI ◽

Takehito SATO ◽

Yoshihiro KUMAGAI ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

T Cell Receptor ◽

Cd4 T Cells ◽

Cell Receptor ◽

Proliferation Ability

Download Full-text

Ig-specific T cell receptor-transgenic T cells are not deleted in the thymus and are functional in vivo.

Journal of Experimental Medicine ◽

10.1084/jem.183.1.203 ◽

1996 ◽

Vol 183 (1) ◽

pp. 203-213 ◽

Cited By ~ 18

Author(s):

F Granucci ◽

M Rescigno ◽

G Marconi ◽

M Foti ◽

P Ricciardi-Castagnoli

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Transgenic Mice ◽

Transgenic Mouse ◽

T Cell Receptor ◽

Cell Receptor ◽

Cell Receptor Transgenic Mouse

The mechanisms that induce T cell tolerance to circulating self-proteins are still controversial, and both the deletion and selection of autoreactive T cells have been observed in the thymus of transgenic mouse models. To address the question of the induction of tolerance to circulating self-constituents, a T cell receptor-transgenic mouse specific for the serum protein immunoglobulin (Ig) gamma and (IgG2ab) was generated. The choice of an allotype-specific T cell also allowed the generation of transgenic control mice not expressing the self-antigen. It was found that the transgenic T cells were not deleted in the thymus, did not become tolerant in the periphery, and regulated the function of gamma 2ab-positive B cells as shown by the lack of IgG2ab protein in the serum of the transgenic mice. In spite of this activity in vivo, the transgenic T cells did not proliferate in vitro in response to the allotype-specific peptide. Interestingly, antigen-specific T cell proliferation could be restored if the transgenic mice were previously challenged to induce IgG2ab responses. After this challenge, IgG2ab protein in the serum of the transgenic mice could be partially restored, although still remaining much lower than in control mice. In addition, there was a dramatic increase in serum IgE levels, suggesting that newly generated gamma 2ab-secreting B cells can be induced to switch to IgE in the presence of allotype-specific T cells. These results indicate that Ig-specific T cells may represent a late-acting form of T cell help for the regulation of the IgG2a-to-IgE class switch.

Download Full-text

Regulatory CD4+ T Cells Expressing Endogenous T Cell Receptor Chains Protect Myelin Basic Protein–specific Transgenic Mice from Spontaneous Autoimmune Encephalomyelitis

Journal of Experimental Medicine ◽

10.1084/jem.188.10.1883 ◽

1998 ◽

Vol 188 (10) ◽

pp. 1883-1894 ◽

Cited By ~ 234

Author(s):

Danyvid Olivares-Villagómez ◽

Yijie Wang ◽

Juan J. Lafaille

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

Myelin Basic Protein ◽

T Cell Receptor ◽

Cd4 T Cells ◽

Basic Protein ◽

Cell Receptor ◽

Allelic Exclusion ◽

Autoimmune Encephalomyelitis

The development of T cell–mediated autoimmune diseases hinges on the balance between effector and regulatory mechanisms. Using two transgenic mouse lines expressing identical myelin basic protein (MBP)–specific T cell receptor (TCR) genes, we have previously shown that mice bearing exclusively MBP-specific T cells (designated T/R−) spontaneously develop experimental autoimmune encephalomyelitis (EAE), whereas mice bearing MBP-specific T cells as well as other lymphocytes (designated T/R+) did not. Here we demonstrate that T/R− mice can be protected from EAE by the early transfer of total splenocytes or purified CD4+ T cells from normal donors. Moreover, whereas T/R+ mice crossed with B cell–deficient, γ/δ T cell–deficient, or major histocompatibility complex class I–deficient mice did not develop EAE spontaneously, T/R+ mice crossed with TCR-α and -β knockout mice developed EAE with the same incidence and severity as T/R− mice. In addition, MBP-specific transgenic mice that lack only endogenous TCR-α chains developed EAE with high incidence but reduced severity. Surprisingly, two-thirds of MBP-specific transgenic mice lacking only endogenous TCR-β chains also developed EAE, suggesting that in T/R+ mice, cells with high protective activity escape TCR-β chain allelic exclusion. Our study identifies CD4+ T cells bearing endogenous α and β TCR chains as the lymphocytes that prevent spontaneous EAE in T/R+ mice.

Download Full-text

Transient Inhibition of Interleukin 4 Signaling by T Cell Receptor Ligation

Journal of Experimental Medicine ◽

10.1084/jem.192.8.1125 ◽

2000 ◽

Vol 192 (8) ◽

pp. 1125-1134 ◽

Cited By ~ 48

Author(s):

Jinfang Zhu ◽

Hua Huang ◽

Liying Guo ◽

Timothy Stonehouse ◽

Cynthia J. Watson ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cd4 T Cells ◽

Cell Receptor ◽

Mitogen Activated Protein Kinase ◽

Interleukin 4 ◽

Interferon Α ◽

Limiting Factor

Interleukin (IL)-4 and IL-12 together with T cell receptor (TCR) engagement are crucial for the differentiation of CD4+ T cells into T helper (Th)2 or Th1 cells, respectively. Although IL-4 receptors (IL-4Rs) but not IL-12Rs are expressed on naive CD4+ T cells, IL-4 has no apparent advantage over IL-12 in driving naive T cell differentiation when the cells are primed with both IL-4 and IL-12 in vitro. It was found that IL-4–induced phosphorylation of Janus kinases 1 and 3, IL-4Rα, signal transducer and activator of transcription 6, and insulin receptor substrate 2 was strikingly but transiently inhibited by TCR ligation both in conventional and TCR transgenic T cells. TCR engagement also blocked the expression of an IL-4–inducible gene. Signals induced by other cytokines, including IL-2, IL-6, and interferon α, but not by insulin-like growth factor 1, were also blocked by TCR engagement. The capacity of various inhibitors to reverse TCR-mediated inhibition of IL-4 signaling suggested that activation of the Ras–mitogen-activated protein kinase pathway and of the calcineurin pathway contribute to desensitizing IL-4R. IL-4 responsiveness returned at about the time (∼12 h) that IL-12–mediated signaling was first observed. Thus, through different mechanisms, neither IL-4R nor IL-12R has any clear advantage in polarizing cells; rather, the availability of cytokine is probably the limiting factor in this process.

Download Full-text