Exaggerated and persistent cutaneous delayed-type hypersensitivity in transgenic mice whose epidermal keratinocytes constitutively express B7-1 antigen.

Nasir, Adnan; Ferbel, Barbara; Salminen, William F.; Barth, Richard K.; Gaspari, Anthony A.

doi:10.1172/jci117411

Cited by 44 publications

(29 citation statements)

References 32 publications

(11 reference statements)

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“…However, class II MHC molecules are upregulated on many nonlymphoid costimulation-deficient tissues during inflammation, and this could serve as a means of terminating chronic T-cell responses. The finding that constitutive expression of B7-1 by keratinocytes greatly increases and prolongs cutaneous delayed-type hypersensitivity reactions to exogenously applied contact sensitizers is consistent with this possibility (83,84).…”

Section: Nonlymphoid Antigenssupporting

confidence: 69%

“…In a normal individual, even if a CD4+ naive T-cell specific for a self peptide-class II MHC complex were to wander into a nonlymphoid tissue, the T cell would not be activated because these tissues normally do not express class II MHC molecules. Evidence for a lack of constitutive self antigen-class II MHC presentation is provided by the finding that transgenic B7 expression alone in pancreatic (3 cells (80-82) or keratinocytes (83,84) does not induce CD4+ T-cell-mediated autoimmunity. It is therefore likely that ignorance is the major mechanism of tolerance for class II MHC-restricted, tissuespecific peptides in normal individuals.…”

Section: Nonlymphoid Antigensmentioning

confidence: 99%

See 1 more Smart Citation

The anatomy of T-cell activation and tolerance.

Mondino

Khoruts²,

Jenkins³

1996

Proc. Natl. Acad. Sci. U.S.A.

206

106

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The mammalian immune system must specifically recognize and eliminate foreign invaders but refrain from damaging the host. This task is accomplished in part by the production of a large number of T lymphocytes, each bearing a different antigen receptor to match the enormous variety of antigens present in the microbial world. However, because antigen receptor diversity is generated by a random mechanism, the immune system must tolerate the function of T lymphocytes that by chance express a self-reactive antigen receptor. Therefore, during early development, T cells that are specific for antigens expressed in the thymus are physically deleted. The population of T cells that leaves the thymus and seeds the secondary lymphoid organs contains helpful cells that are specific for antigens from microbes but also potentially dangerous T cells that are specific for innocuous extrathymic self antigens.

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Section: Nonlymphoid Antigenssupporting

confidence: 69%

Section: Nonlymphoid Antigensmentioning

confidence: 99%

The anatomy of T-cell activation and tolerance.

Mondino

Khoruts²,

Jenkins³

1996

Proc. Natl. Acad. Sci. U.S.A.

206

106

View full text Add to dashboard Cite

show abstract

“…7). Blocking these pathways with a CTLA-4Ig fusion protein or CD154 antibodies can prevent autoimmune disease, autoantibody production, antigen presentation, T cell activation, T cell-B cell interaction and clonal expansion of effector T-cell populations 19,[23][24][25][26][27][28][29] as well as rejection in most transplant models. 30 -34 Therefore, it is quite likely that also in human FHF, an upregulation of CD80/CD86 and CD40 will result in a potent activation of immunocompetent cytotoxic effector cells.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Expression of CD80 (B7-1), CD86 (B7-2), and CD40 and Their Ligands CD28 and CD154 in Fulminant Hepatic Failure

Leifeld

Trautwein

Dumoulin

et al. 1999

The American Journal of Pathology

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To define a possible role for changes in the regulation of antigen presentation in fulminant hepatic failure (FHF) , we studied the expression of co-stimulatory molecules CD80 (B7-1) , CD86 (B7-2) , and CD40 along with their ligands CD28 and CD154. We analyzed the liver tissue from patients with FHF (n ‫؍‬ 18) , chronic liver disease (n ‫؍‬ 30) , and acute hepatitis (n ‫؍‬ 3) and from normal controls (n ‫؍‬ 9) by immunohistochemistry and examined the temporal relationship between CD80/CD86 and CD40 expression and disease in the mouse models of galactosamine-lipopolysaccharide and galactosamine-tumor-necrosis-factor-induced FHF. In human controls , faint CD80/CD86 immunoreactivity was restricted to Kupffer cells, and CD40 expression was expressed on bile ducts , macrophages , and sinusoidal endothelial cells (SECs). In FHF , immunoreactivity for CD80 and CD86 was observed on significantly higher numbers of cells, including SECs. Increased CD80/CD86 expression corresponded to increased numbers of CD28-positive lymphocytes. The expression of CD40 was also clearly elevated on virtually all cell types in FHF. In both murine models , CD40 and CD80/CD86 expression was up-regulated before tissue damage could be detected. Our data suggest that up-regulated expression of co-stimulatory molecules might lead to an excessive antigen presentation in FHF as an early step in the pathogenesis before the onset of tissue damage. (Am J Pathol 1999, 154:1711-1720) Hepatitis B virus infection or drug toxicity can initiate a sequence of severe inflammatory reactions that may lead to rapid organ failure and death. Although the precise pathogenesis is poorly understood, enhanced immune activation, including aberrant antigen presentation and T-cell activation, may essentially contribute to hepatocyte destruction in fulminant hepatic failure (FHF). A balance in the interaction between antigen-presenting cells (APCs) and lymphocytes is of special importance to the liver, as the hepatic immune system is confronted with a high number of antigens that reach the liver via the portal tract and that normally do not elicit immune responses.Recently, it has become evident that a sufficient immune response depends on an efficient T cell activation via co-stimulatory molecules.1-4 The interaction of CD80 (B7-1) and CD86 (B7-2) with their counter-receptors on T lymphocytes (CD28 and CD152) provides a particularly potent co-stimulatory signal, which amplifies the response of T cells. Although antigen presentation followed by co-stimulation induces full T-cell activation, such antigen presentation that lacks co-stimulatory signals results in tolerance or anergy for the specific antigen. [5][6][7] CD80 is a 44-to 60-kd member of the immunoglobulin superfamily with a limited expression on professional APCs such as macrophages, dendritic cells, and activated B cells. CD86 is a 75-to 115-kd cell surface glycoprotein with 25% amino acid homology to CD80. It also has a restricted expression on APCs.Regulation of co-stimulation may also involve the CD40 molec...

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“…59 However, the promoter construct was not identical to the one used by us and by Laufer and colleagues. 8,60 Finally, analysis of murine K14 expression in the thymus revealed its exclusive localization in medullary regions. 61 Taken together, these data suggest that cortical targeting achieved by us and by Laufer and colleagues critically depends on the promoter construct and is not an inherent characteristic of K14 expression.…”

mentioning

confidence: 99%

Dissociation of thymic positive and negative selection in transgenic mice expressing major histocompatibility complex class I molecules exclusively on thymic cortical epithelial cells

Capone

Romagnoli

Beermann

et al. 2001

Blood

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IntroductionBecause of the random nature of T-cell receptor alpha (TCR␣) and TCR␤ gene rearrangements, the developing T-cell repertoire needs to undergo positive and negative selection processes. Thymic positive selection is thought to enrich for T cells expressing a clonotypic TCR␣␤ capable of interaction with self-major histocompatibility complex (MHC) heterodimers, although alternative views exist. Thymic negative selection eliminates or inactivates selfreactive T lymphocytes through induction of apoptosis and anergy. Although negative selection probably rids the developing T-cell repertoire of the majority of self-reactivity, peripheral tolerance mechanisms survey remaining self-specific T-cell clones. The resulting peripherally circulating T-cell repertoire is capable of recognition of foreign, but not self-peptides presented by self-MHC molecules. [1][2][3][4][5] Because thymic positive and negative selection both involve TCR-MHC/peptide interactions, an important issue is what determines the outcome of such an interaction. Initially, studies have focused on the thymic stromal cell types involved in thymic selection. It has been known that MHC/peptide complexes expressed on cortical epithelium are capable of positive selection of conventional TCR␣␤ ϩ thymocytes, whereas medullary epithelium as well as antigen-presenting cells (APCs) of hematopoietic origin cannot, 6-8 although quantitatively minor exceptions to this rule have been reported. 9,10 On the other hand, negative selection is known to be mediated primarily by APCs of hematopoietic origin (reviewed in Anderson et al 1 and Laufer et al 11 ).Given the fact that thymic epithelium can induce positive selection while APCs cannot, it was conceivable that differences in the repertoire of presented peptides play a role in the outcome of a TCR-MHC/peptide interaction. Although peptide elution studies from epithelial cells and APCs have thus far failed to confirm this hypothesis, 12 several lines of evidence indicate that thymic epithelial cells have specialized antigen presentation properties and may present different peptides from those presented by professional APC. [13][14][15][16][17][18] Therefore, an interaction with MHC/peptide ligands expressed by thymic epithelial cells may allow for positive selection, and these cells would subsequently not be negatively selected because the same ligand is not expressed on cells capable of negative selection. However, in mice expressing MHC class II molecules loaded with a single peptide CD4 ϩ T lymphocytes develop, [19][20][21][22][23] demonstrating that possible differences in the repertoire of peptides presented by positively and negatively selecting cell types alone cannot fully explain the positive/negative selection paradox.An alternative hypothesis on the mechanism of thymic positive/ negative selection states that the intensity of TCR triggering determines the selection outcome. A high avidity interaction would lead to negative selection, a very weak signaling to death by neglect, whereas an intermediate ...

show abstract

Exaggerated and persistent cutaneous delayed-type hypersensitivity in transgenic mice whose epidermal keratinocytes constitutively express B7-1 antigen.

Cited by 44 publications

References 32 publications

The anatomy of T-cell activation and tolerance.

The anatomy of T-cell activation and tolerance.

Enhanced Expression of CD80 (B7-1), CD86 (B7-2), and CD40 and Their Ligands CD28 and CD154 in Fulminant Hepatic Failure

Dissociation of thymic positive and negative selection in transgenic mice expressing major histocompatibility complex class I molecules exclusively on thymic cortical epithelial cells

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