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(Journal of Leukocyte Biology. 2001;70:185-191.)
© 2001 by Society for Leukocyte Biology

Insights into molecular mechanisms of contact hypersensitivity gained from gene knockout studies

Binghe Wang*, Claudio Feliciani{dagger}, Irwin Freed*, Qinchao Cai* and Daniel N. Sauder*

* Division of Dermatology, Sunnybrook and Women’s College Health Science Centre, University of Toronto, Ontario, Canada M4N 3M5, and
{dagger} Department of Dermatology, University "G.d’Annunzio", Via dei Vestini Chieti, Italy

Correspondence: Dr. Daniel N. Sauder, Professor and Chairman, Johns Hopkins University, Suite 1002, 550 N. Broadway, Baltimore, MD 21205. E-mail: dsauder{at}jhmi.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 REFERENCES
 
Contact hypersensitivity (CHS), a dendritic-cell (DC)-dependent, T-cell-mediated skin immune response to reactive haptens, has been a subject of intense research for many years. The molecular mechanisms underlying CHS are complicated and are not fully understood. During the past few years, varieties of gene-targeted knockout mice have been used in the study of CHS. Such studies have contributed significantly to our understanding of the mechanisms responsible for the initiation of CHS. This review focuses on insights into molecular requirements for CHS gained from knockout studies.

Key Words: dendritic cell • hapten • CHS • mouse • targeted mutation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
REFERENCES
 
Contact hypersensitivity (CHS) is a T-cell-mediated cutaneous immune response to reactive haptens. After exposure of the skin to contact allergens, haptens covalently bind to discrete amino acid residues on carrier proteins. The epidermal Langerhans cell (LC), a member of the dendritic-cell (DC) family, takes up haptenated proteins and processes them into antigenic peptides which are transported to the cell surface in association with major histocompatibility complex (MHC) class I or class II molecules [1 , 2 ]. LCs then migrate into the skin-draining lymph node (LN) to present the antigenic peptide to naïve T cells. As a result, T cells become activated and clonally expanded (afferent phase). When the skin is challenged with relevant haptens, LCs and/or other antigen-presenting cells present it to recruited hapten-specific T cells. As a result, these T cells are activated and induced to produce cytokines and chemokines, with the subsequent recruitment of a variety of bystander cells including macrophages, thereby initiating cutaneous inflammatory reactions (efferent phase) [3 , 4 ].

CHS has been a subject of intense research for many years. Since the first experimental animal model for CHS was reported in 1926, mouse CHS models have been widely used in studies concerning its pathophysiology. To induce CHS, mice are usually sensitized by painting hapten on the shaved abdomen skin and 5 days later are challenged with the same hapten on the ear. The reactive haptens commonly used include oxazolone (OX), dinitrochlorobenzene, dinitrofluorobenzene (DNFB), trinitrochlorobenzene, picryl chloride (PI), and fluorescein isothiocyanate (FITC). The CHS response is usually evaluated by measurement of ear swelling at 24 h after challenge. This mouse CHS model has significantly contributed to CHS research. However, the complicated mechanism underlying CHS is not fully understood. Recently, the study has been made easier with the advent of gene-targeted knockout (KO) technology, which can be used to deplete selective molecules of interest from experimental animals [5 ]. During the past few years, more than 50 kinds of gene KO mice have been used as experimental models to define the role of respective molecules in CHS responses. This article reviews recent advances in our understanding of the molecular mechanisms of CHS gained from gene KO studies, with particular regard to the interaction between T-cell receptors (TCRs) and the MHC-peptide complex, the roles of costimulatory molecules and adhesion molecules, and the involvement of cytokines and chemokines in CHS responses.

Effects of deficiency with TCRs, coreceptors, or MHC on CHS
Antigen presentation and T-cell activation require two signals [6 ]. The interaction of TCR{alpha}ß heterodimers and their coreceptors, CD4 and CD8, with the MHC-peptide complex releases signal 1. Interaction of costimulatory molecules with their receptors releases signal 2. The crucial role of signal 1 in CHS initiation has been demonstrated by studies on TCR{alpha} chain KO mice (with deficiency in {alpha}ß T cells) and MHC class I and II double-KO mice (Table 1). CHS responses were abolished in TCR{alpha} KO mice, confirming {alpha}ß T cells as the critical effector cells for CHS [7 ]. CHS responses were abolished in MHC class I and II double-KO mice as well, supporting the crucial role of the interaction between TCR{alpha}ß and MHC in CHS initiation [8 ]. In contrast, CHS responses were normal in TCR{delta} chain KO mice (with deficiency in {gamma}{delta} T cells) (on C57BL/6 background) or even enhanced (on FVB background) [9 , 10 ].


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  		Table 1. Knockouts Deficient in TCR, Coreceptors, or MHC

 
The T-cell coreceptors CD4 and CD8 stabilize and increase the avidity of interaction between TCR{alpha}ß and peptide-MHC determinants on antigen-presenting cells. CD4+ T cells recognize peptides in the antigen-binding pocket of MHC class II molecules, whereas CD8+ T cells recognize peptides in the antigen-binding pockets of MHC class I molecules. The relative role of CD4+ T helper (Th) cells versus CD8+ cytotoxic T (Tc) cells in CHS remains controversial. Observations that CHS responses were depressed in CD4 KO mice (with deficiency in CD4+ T cells) and normal in MHC class I KO mice support the traditional view that CHS represents the prototype of delayed-type hypersensitivity (DTH), which is mediated by CD4+ T cells [11 , 12 ]. Observations that CHS responses were abolished in MHC class I KO mice but enhanced in class II KO mice support the notion that CHS responses are mediated by CD8+ T cells and down-regulated by CD4+ T cells [8 ]. The conflicting results may be caused by the great diversity in mouse CHS responses, which vary depending on the mouse genetic background and the type of hapten used [13 ].

Recently, we have demonstrated that both CD4 KO mice (lacking CD4+ T cells) and CD8 KO mice (lacking CD8+ T cells) have a decreased CHS response to DNFB and OX, as compared with wild-type (WT) mice [13 ]. Moreover, time course experiments showed that the duration of the CHS response was shortened in CD4 KO and CD8 KO mice. The LN cells from hapten-sensitized CD4 KO and CD8 KO mice showed a decreased capacity for transferring CHS, suggesting that the CHS defect occurs in the sensitization phase in these mutants. In vitro depletion of either CD4+ T cells from CD8 KO LN cells or CD8+ T cells from CD4 KO LN cells resulted in a complete loss of CHS transfer. Furthermore, both CD4+ Th1 and CD8+ Tc1 cells in the skin-draining LNs produced significant amounts of interferon (IFN) {gamma}. These results suggest that both CD4+ Th1 and CD8+ Tc1 cells play a crucial role in the full development of CHS.

Costimulatory molecules and adhesion molecules in CHS
T-lymphocyte activation requires not only antigen binding but also a costimulatory signal, usually delivered by interactions between B7 molecules on DCs and CD28 molecules on T cells [14 , 15 ]. Studies using B7 KO and CD28 KO mice confirmed the important role of costimulatory molecules in CHS responses (Table 2 ). B7-1 KO mice had a normal CHS [16 ]. B7-2 KO mice demonstrated a modestly reduced CHS response only at very low doses of OX (0.05%) but responded normally at higher OX doses [16 ]. The CHS response to OX was significantly diminished in B7-1/B7-2 double-KO mice [16 ]. Moreover, CD28 KO mice demonstrated a significant depression in CHS responses to DNFB and OX [17 ]. Although important, B7/CD28 interaction is not necessary for CHS responses. The inhibition of CHS response to OX in B7-1/B7-2 double-KO mice was largely overcome at higher doses of the hapten, indicating the presence of compensatory pathways.


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  		Table 2. Knockouts Lacking Costimulatory or Adhesion Molecules

 
In fact, a recent study has demonstrated that another costimulatory pathway, Ox40/Ox40L, is also involved in the initiation of CHS, because Ox40L KO mice exhibit impaired CHS responses to OX at either low (0.05%) or high (1.0%) doses. This significant decrease in CHS responses is also observed when DNFB or FITC is used as the allergen [18 ]. Those authors further examined whether the defect seen in CHS in Ox40L KO mice occurs in the sensitization or challenge phases, by cell transfer experiments. Draining LN cells from OX-sensitized Ox40L KO and WT mice were adoptively transferred into naïve WT and Ox40L KO recipients. They found that WT mice adoptively transferred with sensitized Ox40L-/- LN cells have significantly decreased CHS responses, suggesting that the CHS defect in Ox40L KO mice occurs in the sensitization phase. Moreover, studies have demonstrated a crucial role for the interaction between CD40 and its ligand CD40L in CHS initiation. CD40L KO mice have a defective DC migration associated with decreased CHS response [19 ].

Adhesion molecules control cell to cell attachment as well as cell transendothelial migration, and they play a crucial role in the operation of the immune system. Adhesion molecules include the selectin family, integrin family, and immunoglobulin (Ig) gene superfamily. The selectin family is involved in leukocyte–endothelial-cell adhesion and plays a critical role in leukocyte trafficking. L-selectin KO mice have an impaired CHS response [20 , 21 ]. E-selectin KO and P-selectin KO mice have normal ear-swelling responses, but cellular infiltrates are reduced in P-selectin KO mice [22 , 23 ]. Ear-swelling responses are significantly decreased in E-/P-selectin double-KO mice. In addition, microabscesses and infiltrating cells are reduced on the ears of double mutants. T cells from E-/P-selectin-deficient mice transfer OX reactivity into naïve WT mice. However, when donor cells from WT mice are transferred into E-/P-selectin-deficient mice, the CHS response is significantly impaired, suggesting that the CHS defect in E-/P-selectin-deficient mice occurs in the challenge phase [22 ].

The integrin family is involved in both cell-matrix and cell-cell interactions. The CHS response is abolished in the ß2-integrin lymphocyte function-associated antigen-1 (LFA-1) {alpha} chain KO mice [24 ] and decreases in {alpha}1-integrin KO mice [25 ]. Intercellular adhesion molecule-1 (ICAM-1) belongs to the Ig gene superfamily. CHS responses are significantly decreased in ICAM-1 KO mice [26 , 27 ], confirming the important role of the interaction between ICAM-1 and its ligand LFA-1 in cutaneous inflammatory reactions. When ICAM-1 and L-selectin are double deficient, the CHS response is virtually abolished [28 ]. Platelet/endothelial cell adhesion molecule-1 (PECAM-1) is not required for the development of CHS because PECAM-1 KO mice are able to mount a normal CHS response [29 ].

Cytokines and chemokines in CHS
On antigen recognition, CD4+ or CD8+ T cells are induced to differentiate into distinct functional subsets, type 1 (Th1 or Tc1) and type 2 (Th2 or Tc2) [30 , 31 ]. Type-1 cells secrete interleukin (IL)-2 and IFN{gamma}, whereas type-2 cells secrete IL-4, IL-5, and IL-10. It is generally believed that type 1 cytokines play effector roles in CHS, whereas type 2 cytokines play a regulatory role. However, some studies suggest that CHS is not necessarily a Th1 response. Different types of allergens may result in qualitatively different immune responses characteristic of selective Th1 and Th2 activation, respectively. Contact allergens such as OX and DNFB preferentially induce Th1-predominant responses, whereas respiratory allergens such as trimellitic anhydride induce Th2-predominant responses [32 ]. Exceptionally, the contact allergen FITC may also induce a Th2 response [33 ].

The effector role of IFN{gamma} in CHS has been confirmed by the demonstration of an impaired CHS response in KO mice lacking IFN{gamma} receptor 2 (IFN{gamma}R2) (Table 3) [34 ]. However, unexpectedly CHS responses are normal in IFN{gamma} KO mice [35 ]. IL-2 is not necessary for CHS initiation because IL-2 KO mice have a normal CHS response [36 ]. The down-regulatory role of the type 2 cytokine IL-10 has been confirmed by the demonstration of an enhanced CHS response to OX and FITC in IL-10 KO mice, increased in both magnitude and duration compared with that in WT mice. Mixed cell infiltration in the ears of IL-10 KO mice has been found to be more severe that that seen in WT mice [37 , 38 ]. However, IL-4 KO mice show a normal CHS response to OX but decreased CHS response to dinitrochlorobenzene, implying an effector role of the Th2 cytokine in CHS response [39 ]


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  		Table 3. Mice Deficient in Cytokines, Chemokines or Their Receptors

 
IL-1, IL-6, and TNF-{alpha} are important proinflammatory cytokines involved in CHS responses. In the skin, IL-1ß, IL-6, and TNF-{alpha} are mainly derived from LCs [40 , 41 ]. IL-1ß KO mice have a normal response to OX but a decreased response to trinitrochlorobenzene [42 , 43 ]. IL-6 KO mice have defective CHS responses to DNFB and OX [36 ]. The important role of TNF-{alpha} signaling has been demonstrated by studies on mice lacking TNF-{alpha} or its receptor (TNFR). TNF-{alpha} KO mice have a decreased CHS response to OX [44 ]. TNFR1 KO mice demonstrate an enhanced CHS response [45 ], whereas TNFR2 KO mice show a decreased LC migration and a depressed CHS response [46 ].

Studies have also suggested that other cytokines may be involved in CHS responses. For example, IL-3 is a hematopoietic growth factor. It is interesting that hematopoiesis is not impaired in IL-3 KO mice, but CHS reactions are compromised [47 ].

Chemokines represent a family of chemotactic proteins that mediate their effect by binding to specific receptors expressed on target cells [48 , 49 ]. Based on a cysteine motif, CXC, CC, C, and CX3C families have been identified. Monocyte chemoattractant protein 1 is a CC chemokine that attracts monocytes, memory T lymphocytes, and natural killer cells. Monocyte chemoattractant protein-1 KO mice show impaired cellular infiltrates in CHS lesions, although the ear-swelling response is normal [50 ]. The CC chemokine receptor (CCR) 5 and CCR6 are expressed on T cells and immature DCs, whereas CCR7 is expressed on mature DCs. Inflammatory stimuli cause epidermal LCs to down-regulate CCR5 and CCR6 while up-regulating CCR7, thus directing the migration of LC from the epidermis into regional LNs. The CHS response is enhanced in CCR5 KO mice [51 ] and CCR6 KO mice [52 ] but is abolished in CCR7 KO mice [53 ].

Effects of miscellaneous mutations on CHS
Various components of the complement system have been implicated in CHS initiation (Table 4). C5a receptor (C5aR) KO mice have an impaired CHS [10 ]. Ig heavy-chain-6 (Igh-6) KO mice are deficient in B-cells. Unexpectedly, the CHS response is decreased in these mice. This does not reasonably suggest an effector role of B cells but may be related to the involvement of complement-fixing Igs in CHS response [54 ]. CD8+ T cells mediate cytotoxicity via two pathways: the perforin pathway and the Fas/FasL pathway. Perforin KO mice, spontaneous mutant Fas-deficient lpr mice, and FasL-deficient gld mice had normal CHS responses; however, perforin KO/gld mice (double deficient in perforin and FasL) did not show any CHS response [55 ], which suggests that CHS requires cytotoxic-activity pathways.


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  		Table 4. CHS in a Miscellaneous Collection of Knockouts

 
Thy-1 (CD90) is a cell surface molecule expressed on murine T cells. Thy-1 KO mice had a reduced CHS response, suggesting that Thy-1 plays a role in CHS [56 ]. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that can degrade cell extracellular matrix and play an important role in the migration of T lymphocytes and macrophages. MMP-3 (stromelysin-1) KO mice show a markedly impaired CHS response [57 ]. MMP-9 (gelatinase B) KO mice exhibit normal ear swelling, but the response persists longer [57 ]. These results indicate that MMPs serve important functions in CHS. MMP-3 is required for CHS initiation, whereas MMP-9 plays a critical role in its resolution. Tenascin-C is an extracellular matrix glycoprotein. Tenascin-C KO mice mount an enhanced CHS response, suggesting a role of tenascin-C in cutaneous inflammatory responses [58 ].

The RelB gene encodes a transcription factor that belongs to the family of nuclear factor (NF)-{kappa}B/Rel proteins. RelB KO mice had an impaired CHS response [59 ]. Signal transducer and activator of transcription 6 plays a central role in the signaling pathways of IL-4 and IL-13. Signal transducer and activator of transcription 6 KO mice demonstrate a reduced CHS response, suggesting that Th2 cytokines play an effector role in CHS [60 ]. The proteins encoded by recombination-activating gene (RAG) make important contributions to the V(J)D recombination. The LCs from RAG2 KO mice fail to elicit a CHS response [61 ]. Leukotrine (LT) B4 is a potent inflammatory mediator; however, LTA4 hydrolase KO mice (lacking LTB4) have a normal CHS response [62 ]. IL-1 receptor-associated kinase (IRAK) is involved in IL-1 and IL-18 signal transduction. IRAK KO mice, however, have a normal CHS response to DNFB, suggesting the presence of an IRAK-independent pathway [63 ].

The {gamma} subunit of the Fc receptor for Igs (FcR{gamma}) is an essential component of the high-affinity receptor for IgE Fc{varepsilon}RI and the low-affinity receptor for IgG (Fc{gamma}RIII) [64 , 65 ]. Targeted disruption of {gamma} chain results in a decreased CHS response [66 ]. Sensory nerve-derived neuropeptides such as substance P demonstrate a member of proinflammatory bioactivities. The cell surface metalloprotease-neutral endopeptidase (NEP) is the principal proteolytic substance P-degrading enzyme. The CHS response is 2.5-fold higher in NEP KO mice, indicating that NEP and cutaneous neuropeptides have a significant role in CHS [67 ]. The IFN-induced and dsRNA-activated kinase (PKR) is a well-characterized component of IFN-regulated antiviral and antiproliferative responses. PKR may also play a role in the regulation of immune responses. When compared with the response in WT mice, the magnitude of CHS response in PKR KO mice is twofold higher and of extended duration, indicating that PKR plays a negative role in the regulation of CHS [68 ]. Caspase-1 [also known as IL-1ß-converting enzyme (ICE)] is capable of generating the mature forms of IL-1ß and IL-18 from their immature precursors. A recent study demonstrated that caspase-1 KO mice had an impaired LC migration and depressed CHS responses to DNFB and OX, indicating that caspase-1 may play an important role in CHS through the regulation of LC [69 ].

Summary and Conclusions
CHS, clinically presenting as allergic contact dermatitis, is one of the most frequent and vexing dermatological problems. The mechanisms underlying CHS are more complicated than we originally thought (i.e., a prototype of DTH). With the advent of gene-targeting technology, a considerable number of studies have used gene KO mice to assess the contribution of respective gene products to the development of CHS response. CHS research has been revolutionized by such studies, which have yielded predicted and unexpected findings and challenged previous ideas.

We now propose that CHS is a DC-dependent, {alpha}ß cell-mediated, heterogeneous skin immune response to contact haptens. CHS differs from classic DTH responses. DTH is mediated by CD4+ Th cells, whereas both CD4+ Th cells and CD8+ Tc cells can function as effector cells for CHS. Various molecules are involved in the development of CHS, including costimulatory molecules, adhesion molecules, cytokines, and chemokines. The CHS response is not necessarily mediated by type-1 cytokines. Th2 cytokine patterns may also occur in CHS, depending on the mouse strain or the hapten used. Moreover, MMP, neuropeptides, and other molecules may also regulate the development of CHS.

Overall, although recently gene knockouts have been widely utilized in CHS research and have made significant contributions, a thorough understanding of the molecular mechanisms of CHS remains distant.


   ACKNOWLEDGEMENTS
 
This work was supported by the Medical Research Council of Canada and the Canadian Dermatology Foundation.

Received December 18, 2000; revised March 31, 2001; accepted April 5, 2001.


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