Peptide Immunization Indicates that CD8+ T Cells are the Dominant Effector Cells in Trinitrophenyl-Specific Contact Hypersensitivity

Martin, Stefan F.; Lappin, Michael B.; Kohler, Jochen; Delattre, Virginie; Leicht, Cornelia; Preckel, Tobias; Simon, Jan C.; Weltzien, Hans Ulrich

doi:10.1046/j.1523-1747.2000.00038.x

Cited by 73 publications

(66 citation statements)

References 24 publications

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“…To address this knowledge gap, we sought to determine the effects of cell type-specific p38α deficiency on contact hypersensitivity (CH). In this skin immune reaction, topical contact with a small-molecule allergen (hapten) leads to a priming of specific T cells (sensitization phase); the resulting effector T cells, particularly CD8 + effectors (12)(13)(14)(15), are recruited to and activated in the skin upon reencounter with the hapten, a process associated with actual skin disease (challenge phase).…”

Section: Resultsmentioning

confidence: 99%

Cell type-specific targeting dissociates the therapeutic from the adverse effects of protein kinase inhibition in allergic skin disease

Ritprajak

Hayakawa²,

Sano³

et al. 2012

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

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The kinase p38α, originally identified because of its endotoxinand cytokine-inducible activity and affinity for antiinflammatory compounds, has been posited as a promising therapeutic target for various immune-mediated disorders. In clinical trials, however, p38α inhibitors produced adverse skin reactions and other toxic effects that often outweighed their benefits. Such toxicity may arise from a perturbation of physiological functions unrelated to or even protective against the disease being treated. Here, we show that the effect of interfering with p38α signaling can be therapeutic or adverse depending on the targeted cell type. Using a panel of mutant mice devoid of p38α in distinct cell types and an experimental model of allergic skin disease, we find that dendritic cell (DC)-intrinsic p38α function is crucial for both antigen-specific T-cell priming and T-cell-mediated skin inflammation, two independent processes essential for the immunopathogenesis. By contrast, p38α in other cell types serves to prevent excessive inflammation or maintain naïve T-cell pools in the peripheral lymphoid tissues. These findings highlight a dilemma in the clinical use of p38α inhibitors, yet also suggest cell-selective targeting as a potential solution for improving their therapeutic index.allergic contact dermatitis | contact hypersensitivity | hapten T he kinase p38α, the most abundant and ubiquitously expressed p38 MAP kinase isoform in mammals, was discovered based on its binding affinity for antiinflammatory compounds (1). The nature of the stimuli that elicited p38α activation and enabled its identification-proinflammatory cytokines, microbial products, and injurious environmental insultsalso hinted at a role for p38α in the immune and stress response (2-4). Pharmacological inhibition of p38α has since held promise for the treatment of allergic, autoimmune, and other diseases of inflammatory etiology. A series of recent clinical studies, however, revealed the frequent occurrence of adverse events, ranging from skin rashes to liver damage, after the use of p38α inhibitors (5-7). These toxicities limited the dose and frequency of p38α inhibitor treatment and have become a liability to fulfilling its promise as an effective therapeutic strategy.The therapeutic index is a relative measure of the efficacy versus toxicity of a treatment regimen. Toxic side effects have often been the cause of the failure of an otherwise effective therapeutic agent such as p38α inhibitors. We questioned whether the adverse effects of p38α inhibitors arose from interference with a physiological function of the protein kinase and, if so, whether the therapeutic and the adverse effects of p38α inhibition were based on distinct cell type-specific mechanisms. In this study, we used a mouse model of allergic contact dermatitis to examine the disease responses of conditional p38α knockout (KO) mice. In these mice, ablation of p38α expression was targeted to keratinocytes, myeloid cells, dendritic cells, or T cells, which represented a simulation of p38...

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Section: Resultsmentioning

confidence: 99%

Cell type-specific targeting dissociates the therapeutic from the adverse effects of protein kinase inhibition in allergic skin disease

Ritprajak

Hayakawa²,

Sano³

et al. 2012

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

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“…The implication is that CD4 π effector cells mediated the response. In contrast, however, when the same peptides were administered to mice in the context of DC, then only class I-binding TNP-peptides induced contact hypersensitivity, and of a magnitude comparable with that observed following conventional topical sensitization (32). The important conclusions that can be drawn from these experiments are that CD8 π may be potent effectors of contact hypersensitivity, but that CD4 π may be active also, and the way in which the inducing antigen is delivered to the immune system (presumably related to the mechanism of MHC loading) can have an important influence on whether CD8 π or CD4 π T lymphocytes predominate as effector cells.…”

Section: Cd8 π Effector Cells and Interplay With Cd4 π Cellsmentioning

confidence: 85%

“…This is despite the fact that in some cases it appears possible to generate CD8 π T lymphocyte responses to skin sensitizing chemicals in the absence of antigen-activated CD4 π cells (28,31). In this context, an investigation of CD4 π /CD8 π selectivity for contact hypersensitivity conducted in immunologically intact mice is instructive (32). Trinitrophenyl (TNP)-derivatized peptides that have affinity for either class I or class II MHC molecules were used.…”

Section: Cd8 π Effector Cells and Interplay With Cd4 π Cellsmentioning

confidence: 99%

Allergic contact dermatitis: the cellular effectors

2002

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Contact hypersensitivity reactions are mediated by lymphocytic effector cells. Until recently it was believed that the most important of these were CD4 π T lymphocytes. However, there is growing evidence that in many instances the predominant effector cell may be a CD8 π T lymphocyte, with in some instances CD4 π cells performing a counter-regulatory function. Here we review the roles of CD4 π T helper (Th) cells and CD8 π T cytotoxic (Tc) cells, and their main functional subpopulations (respectively, Th1 and Th2 cells and Tc1 and Tc2 cells) in the elicitation of contact hypersensitivity reactions and consider the implications of effector cell selectivity for the biology of allergic contact dermatitis.

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“…This work demonstrated that the CD4 + T cell population critical for the initiation of a CS response represents only a small proportion of the total number of adherent leukocytes in the inflamed dermal microvasculature. However, CD8 + T cells have also been shown to play important effector roles in CS (40,41). Therefore, in this study we used this approach to examine adhesion of CD8 + T cells in addition to CD4 + T cells and neutrophils in the two-challenge CS model ( Fig.…”

Section: Neutrophil and Cd8 + T Cell Adhesion Are Blunted In Multiplementioning

confidence: 99%

Endogenous Regulatory T Cells Adhere in Inflamed Dermal Vessels via ICAM-1: Association with Regulation of Effector Leukocyte Adhesion

Deane

Abeynaike

Norman

et al. 2012

The Journal of Immunology

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Regulatory T cells (Tregs) must express appropriate skin-homing adhesion molecules to exert suppressive effects on dermal inflammation. However, the mechanisms whereby they control local inflammation remain unclear. In this study we used confocal intravital microscopy in wild-type and Foxp3-GFP mice to examine adhesion of effector T cells and Tregs in dermal venules. These experiments examined a two-challenge model of contact sensitivity (CS) in which Treg abundance in the skin progressively increases during the course of the response. Adhesion of CD4+ T cells increased during CS, peaking 8–24 h after an initial hapten challenge, and within 4 h of a second challenge. At these time points, 40% of adherent CD4+ T cells were Foxp3+ Tregs. CD4+ T cell adhesion was highly dependent on ICAM-1, and consistent with this finding, anti–ICAM-1 prevented Treg adhesion. Skin TGF-β levels were elevated in skin during both challenges, in parallel with Treg adhesion. In the two-challenge CS model, inhibition of ICAM-1 eliminated Treg adhesion, an effect associated with a significant increase in neutrophil adhesion. Similarly, total CD4+ T cell depletion caused an increase in adhesion of CD8+ T cells. Because Treg adhesion was restricted by both of these treatments, these experiments suggest that adherent Tregs can control adhesion of proinflammatory leukocytes in vivo. Moreover, the critical role of ICAM-1 in Treg adhesion provides a potential explanation for the exacerbation of inflammation reported in some studies of ICAM-1–deficient mice.

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Peptide Immunization Indicates that CD8+ T Cells are the Dominant Effector Cells in Trinitrophenyl-Specific Contact Hypersensitivity

Cited by 73 publications

References 24 publications

Cell type-specific targeting dissociates the therapeutic from the adverse effects of protein kinase inhibition in allergic skin disease

Cell type-specific targeting dissociates the therapeutic from the adverse effects of protein kinase inhibition in allergic skin disease

Allergic contact dermatitis: the cellular effectors

Endogenous Regulatory T Cells Adhere in Inflamed Dermal Vessels via ICAM-1: Association with Regulation of Effector Leukocyte Adhesion

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