IL-4 Enhances Keratinocyte Expression of CXCR3 Agonistic Chemokines

108

Activation and skin-selective homing of T cells and their effector functions in the skin represent sequential immunological events in the pathogenesis of atopic dermatitis (AD). Apoptosis of keratinocytes, induced mainly by T cells and mediated by IFN-γ and Fas, is the essential pathogenetic event in eczema formation. Keratinocyte apoptosis appears as activation-induced cell death in AD. By IFN-γ stimulation, chemokines such as IFN-γ-inducible protein 10, monokine induced by IFN-γ, and IFN-γ-inducible α-chemoattractant are strongly up-regulated in keratinocytes. These chemokines attract T cells bearing the specific receptor CXCR3, which is highly expressed on T cells isolated from skin biopsies of AD patients. Accordingly, an increased T cell chemotaxis was observed toward IFN-γ-treated keratinocytes. Supporting these findings, enhanced IFN-γ-inducible protein 10, monokine induced by IFN-γ, and IFN-γ-inducible α-chemoattractant expression was observed in lesional AD skin by immunohistochemical staining. These results indicate a second step of chemotaxis inside the skin after transendothelial migration of the inflammatory cells. Keratinocytes undergoing apoptosis in acute eczematous lesions release chemokines that attract more T cells toward the epidermis, which may further augment the inflammation and keratinocyte apoptosis.

Section: Discussionmentioning

confidence: 99%

A Second Step of Chemotaxis After Transendothelial Migration: Keratinocytes Undergoing Apoptosis Release IFN-γ-Inducible Protein 10, Monokine Induced by IFN-γ, and IFN-γ-Inducible α-Chemoattractant for T Cell Chemotaxis Toward Epidermis in Atopic Dermatitis

Klunker¹,

Trautmann²,

Akdiş³

et al. 2003

108

“…In contrast, keratinocytes appear to be resistant to Th2-mediated cytotoxicity. Alternatively, Th1 and Th2 cells can effectively contribute to disease expression by inducing keratinocyte release of chemokines that attract T cells in the skin (17,25) and by rendering keratinocytes more susceptible to CTL activity.…”

Section: Discussionmentioning

confidence: 99%

“…Keratinocytes are profoundly involved in the elicitation and effector phase of ACD, because they secrete cytokines and chemokines that effectively activate resident dendritic cells and endothelial cells and contribute to lymphocyte recruitment into the skin (17,(23)(24)(25). Keratinocytes, under the influence of lymphocytederived cytokines such as IFN-␥ and IL-17, also express MHC class II and adhesion molecules (ICAM-1) crucial for T cell function and retention in the epidermis (17,26).…”

Section: A Llergic Contact Dermatitis (Acd)mentioning

confidence: 99%

Disparate Cytotoxic Activity of Nickel-Specific CD8+ and CD4+ T Cell Subsets Against Keratinocytes

Traidl

Sebastiani

Albanesi

et al. 2000

Self Cite

137

115

Allergic contact dermatitis (ACD) is the result of an exaggerated immune reaction to haptens mediated by skin-homing T cells, but the effector mechanisms responsible for the tissue damage are poorly understood. Here we studied the capacity of distinct subsets of hapten-specific T cells to induce apoptosis in autologous keratinocytes. Skin- and blood-derived nickel-specific CD8+ T cytotoxic 1 (Tc1) and Tc2 clones as well as CD4+ Th1 and Th2 expressed the cutaneous lymphocyte-associated Ag and exhibited strong MHC-restricted cytotoxicity against nickel-coupled B lymphoblasts, as detected by the [3H]TdR release assay. Both Tc1 and Tc2 clones, but not CD4+ T cells, displayed a significant cytotoxic activity against resting nickel-modified keratinocytes. Following IFN-γ treatment, keratinocytes expressed MHC class II and ICAM-1 and became susceptible to Th1-mediated, but not Th2-mediated, cytotoxicity. The molecules of the two major cytotoxic pathways, Fas ligand (FasL) and perforin, were expressed by Tc1, Tc2, and Th1 cells, whereas Th2 cells expressed only FasL. Experiments performed in the presence of specific inhibitors of the perforin (concanamycin A) and FasL (brefeldin A) pathway indicated that perforin-mediated killing dominated in Tc1 and Tc2, and FasL-mediated cytotoxicity prevailed in Th2 clones, with a more heterogeneous behavior in the case of Th1 cells. Finally, perforin mRNA was expressed in ACD lesional skin, as assessed by RT-PCR analysis. In aggregate, our results indicate that keratinocytes can be target of multiple hapten-specific CTL responses, that may have distinct roles in the epidermal injury during ACD.

“…Although ACD is considered a Th1-dominated disease, other cytokines, such as IL-4 and IL-17. are abundantly expressed in acute ACD skin, and contribute to disease expression by enhancing the release of CXCR3 agonists induced by IFN-g (10), and by increasing ICAM-1 expression by keratinocyte, respectively (11). Although CD3 + T lymphocytes are the most prominent cellular type recruited in ACD skin, the inflammatory infiltrate also comprises of myeloid and plasmacytoid dendritic cells, as well as NK cells and NK-T lymphocytes (11)(12)(13)(14).…”

Section: Cd56mentioning

confidence: 99%

CD56highCD16−CD62L− NK Cells Accumulate in Allergic Contact Dermatitis and Contribute to the Expression of Allergic Responses

Carbone

Nasorri

Pennino

et al. 2009

Self Cite

Allergic contact dermatitis is a common disease caused by an exaggerated T cell-mediated immune response to skin-applied haptens. We show in this study that NK cells affect skin immune responses to haptens by releasing type 1 cytokines and inducing keratinocytes apoptosis. Immunohistochemical stainings demonstrated that NK lymphocytes constitute ∼10% of the inflammatory infiltrate mostly distributed in the superficial dermis and in the epidermis at the site of intense spongiotic changes. More than 90% of NK cells isolated from allergic contact dermatitis skin showed a CD3-CD56highCD16− phenotype by FACS analysis. In addition, they uniformly expressed NKG2A, intermediate to high levels of perforin, and the activating receptors, NKG2D, NKp44, and NKp46, but lacked NKp30 and killer Ig-related receptors. Skin NK lymphocytes displayed a CXCR3+CCR6+CCR5+ chemokine receptor asset for homing into inflamed skin, but not CD62L and CCR7 for lymph node homing. When NK cells from nickel-allergic donors were exposed in vitro to the metal, they failed to proliferate, to upregulate CD69, and to release IFN-γ, thus indicating that NK lymphocytes do not exhibit memory-like properties to haptens. However, IL-2 released by hapten-driven T lymphocytes rapidly induced the release of IFN-γ by NK cells and promoted the NK-mediated apoptosis of autologous keratinocytes in a hapten-independent manner. Our findings underline the importance of the interaction between innate and adaptive immune mechanisms for amplification of skin allergic responses to haptens and full expression of allergic contact dermatitis