Skin Homing Research Articles

The skin homing receptor cutaneous leucocyte-associated antigen (CLA) is up-regulated byLeishmaniaantigens in T lymphocytes during active cutaneous leishmaniasis

The cutaneous leucocyte-associated antigen receptor (CLA) can direct Leishmania-specific T lymphocytes towards inflamed skin lesions. Homing receptors [CLA, lymphocyte-associated antigen 1 (LFA-1) or CD62L] were analysed in lymphocytes from blood and cutaneous leishmaniasis (CL) lesions. CL patients with active lesions (A-CL) presented lower levels of T lymphocytes expressing the CLA(+) phenotype (T CD4(+) = 10.4% +/- 7.5% and T CD8(+) = 5.8% +/- 3.4%) than did healthy subjects (HS) (T CD4(+) = 19.3% +/- 13.1% and T CD8(+) = 21.6% +/- 8.8%), notably in T CD8(+) (P < 0.001). In clinically cured patients these percentages returned to levels observed in HS. Leishmanial antigens up-regulated CLA in T cells (CLA(+) in T CD4(+) = 33.3% +/- 14.1%; CLA(+) in T CD8(+) = 22.4% +/- 9.4%) from A-CL but not from HS. An enrichment of CLA(+) cells was observed in lesions (CLA(+) in T CD4(+) = 45.9% +/- 22.5%; CLA(+) in T CD8(+) = 46.4% +/- 16.1%) in comparison with blood (CLA(+) in T CD4(+) = 10.4% +/- 7.5%; CLA(+) in T CD8(+) = 5.8% +/- 3.4%). Conversely, LFA-1 was highly expressed in CD8(+) T cells and augmented in CD4(+) T from peripheral blood of A-CL patients. In contrast, CD62L was not affected. These results suggest that Leishmania antigens can modulate molecules responsible for migration to skin lesions, potentially influencing the cell composition of inflammatory infiltrate of leishmaniasis or even the severity of the disease.

Maintenance of Peripheral Tolerance through Controlled Tissue Homing of Antigen-Specific T Cells in K14-mOVA Mice

Immunological tolerance is crucial to avoid autoimmune and inflammatory diseases; however, the mechanisms involved are incompletely understood. To study peripheral tolerance to skin-associated Ags, we generated new transgenic mice expressing a membrane-bound form of OVA in skin under the human keratin 14 (K14) promoter (K14-mOVA mice). In contrast to other transgenic mice expressing similar self-Ags in skin, adoptive transfer of Ag-specific T cells does not induce inflammatory skin disease in our K14-mOVA mice. OVA-specific T cells transferred into K14-mOVA mice are activated in lymphoid tissues, undergo clonal expansion, and eventually acquire effector function. Importantly, these Ag-specific T cells selectively up-regulate expression of E-selectin ligand in cutaneous lymph nodes but not in mesenteric lymph nodes and spleen, demonstrating that expression of endogenous self-Ags in skin dictates imprinting of skin tissue homing in vivo. However, an additional inflammatory signal, here induced by tape stripping, is required in K14-mOVA mice to induce T cell migration to skin and development of inflammatory skin disease. Depletion of regulatory CD4(+)CD25(+) T cells did not provoke homing of transferred T cells to skin under steady-state conditions, indicating that these cells are not the key regulators for inhibiting T cell homing in K14-mOVA mice. Both skin-derived and lymph node-resident CD8alpha(+) dendritic cells are responsible for Ag presentation in vivo and induce tolerance to skin Ags, as we show by selective depletion of langerin(+) and CD11c(+) dendritic cells. Taken together, controlled skin homing of T cells is critical for the maintenance of peripheral immune tolerance to epidermal self-Ags.

Expression of chemokine receptors implicated in skin-homing on Herpesvirus-specific CD8+ T-cells (95.14)

Abstract HSV-2-specific CD8+ T-cells express high levels of cutaneous lymphocyte associated antigen (CLA) and the related E-selectin ligand (ESL). These mediate rolling adhesion to inflamed dermal endothelium. EBV- or CMV-specific CD8+ T-cells express low levels of CLA/ESL. Full arrest and diapedesis are mediated via the chemokine axis. Chemokine receptors implicated in skin homing include CCR4, CCR6, CCR8, CCR10, and CXCR3. We examined cell surface expression of these receptors on pathogen-specific, tetramer-positive CD8 T-cells and bulk CD4 and CD8 T-cells, using both cryopreserved and fresh PBMC. Our results confirm that amongst CD4+ cells, CLA+ cells selectively express CCR4 and CCR10, and extend these findings to bulk CD8+ cells. We did not, however, observe selective enrichment of CCR4 or CCR10 on HSV-2-specific CD8+ T-cells compared to bulk CD4+ or CD8+ T-cells. In contrast, we measured higher CXCR3 expression on HSV-2-specific CD8+ T-cells when compared to bulk CD4+ and CD8+ T-cells, or EBV- or CMV-specific CD8+ T-cells. This suggests HSV-2-specific CD8+ T-cells may utilize CXCR3 expression to home to infected skin lesions. Support from: NIH Grant AI30731 and STD/AIDS Research Training Grant 5T32AI007140

Distinct subsets of human skin dendritic cells differ on their ability to initiate Th17 responses (90.24)

Abstract Activated human cutaneous dendritic cells (DCs) have the ability to initiate Th1 and Th2 immunity. However, whether human cutaneous DCs are capable of biasing pro-inflammatory Th17 responses remains little understood. Utilizing human skin explants composed by both epidermis and dermis or epidermal or dermal sheets to collect activated skin-migratory DCs (smiDCs), we demonstrated that smiDCs stimulate allogeneic naïve CD4+ T cells to differentiate simultaneously into two distinct effector Th17 and Th1 populations with ability of skin homing and inducing severe tissue damage. Of the two main myeloid DC populations resident in the skin, the subset of epidermal skin-migratory Langerhans cells (smiLCs) were capable of inducing Th17 responses. This effect depended on the combined effects of IL-15 and stabilized IL-6 trans-signaling of naïve CD4+ T cells. Purified skin-migratory DDCs did not synthesize IL-15 and were unable to bias Th17 responses however, they acquired the ability to bias Th17 cells in co-cultures with CD4+ T cells supplemented with IL-15 and stabilized IL-6. Overall, our data demonstrate that human cutaneous LCs induce Th17 responses by mechanisms different from those previously described for mouse DCs and human monocytes and highlight the need to target clinical treatments based on these variations. Supported by NIH grants: R01 CA100893 (ATL)

OR.59. Investigating the Role of Skin Homing Vγ9Vδ2 T Cells as Novel Pathogenic Cells in Psoriasis

OR.59. Investigating the Role of Skin Homing Vγ9Vδ2 T Cells as Novel Pathogenic Cells in Psoriasis

Redução dos linfócitos T-CD8+ citotóxicos observada com a terapia Puva em paciente com vitiligo

Na patogênese do vitiligo tem-se enfatizado o papel das células T citotóxicas. Identificadas pelo antígeno linfocitário cutâneo (CLA), essas células já foram descritas no sangue de pacientes com outras dermatoses e podem ser depletadas pela fototerapia concomitantemente à melhora clínica. Descreve-se caso de vitiligo generalizado com melhora clínica expressiva após Puva, no qual houve redução de 25% dos linfócitos T CD8+-CLA+ circulantes.

Skin Homing and Recruitment of Leukocytes in Allergic Contact Dermatitis

Allergic contact dermatitis (ACD) is a common skin disorder that has a high socio-economic impact with regard to the increasing number of industrial allergens that has potential harmful effect on the skin of manual workers. Its management relies on the use of topical anti-inflammatory drugs as well as the avoidance of the allergens inducing the disease. However, with regard to the ubiquitous character of many chemicals in the environment, treatment of the disease remains unsatisfactory. Understanding the molecular basis of the disease is of major importance in prospect of designing new therapeutic modalities. In this article, the various stages of the disease are reviewed as well as the recent advances in the understanding of the molecular basis of the mechanisms of the disease that would help to conceive new concepts for drug intervention. The article also reviews some of the recent patent relevant to the field.

Función efectora de linfocitos T CLA+ sobre queratinocitos autólogos en psoriasis

BackgroundCutaneous lymphocyte antigen (CLA) is expressed by a subgroup of memory T cells that exhibit skin homing and are implicated in cutaneous T-cell-mediated diseases. Material and methodsExpression of genes associated with psoriasis was analyzed in keratinocytes taken from patients and healthy individuals and cultured under different conditions, including activation using supernatants from CLA+ T lymphocytes activated with anti-CD3 and anti-CD28 antibodies. ResultsKeratinocytes from psoriasis patients activated by CLA+ T lymphocytes expressed higher levels of interferon-inducible protein 10, HLA-DR, intercellular cell adhesion molecule 1, and inducible nitric oxide synthase. ConclusionsOur results suggest that we have developed an in vitro model that will allow analysis of the effector role of CLA+ T lymphocytes on keratinocytes in psoriasis. This model may allow the identification of genes involved in the pathology of psoriasis through induction by CLA+ T lymphocytes.

Staphylococcal toxin-induced T cell proliferation in atopic eczema correlates with increased use of superantigen-reactive Vbeta-chains in cutaneous lymphocyte-associated antigen (CLA)-positive lymphocytes.

Staphylococcal superantigens have been implicated in the pathogenesis of atopic dermatitis (AD). This may occur through superantigenic activation of T lymphocytes and their subsequent induction of the skin homing receptor CLA on activated cells. We investigated the proliferative responses of peripheral blood mononuclear cells (PBMC) from 10 patients with an infective exacerbation of AD and six normal controls to the staphylococcal superantigens, staphylococcal enterotoxin A and B (SEA, SEB) and toxic shock syndrome toxin-1 (TSST-1), and the mitogens phytohaemagglutinin (PHA) and concanavalin A (Con A). We also assessed CLA and T cell receptor (TCR) Vbeta-chain expression by immunofluorescence and flow cytometry before and after stimulation. PBMC from AD patients showed two-fold increased proliferation to SEA and SEB (P < 0.01) compared with normals, whereas the response to mitogenic stimulation was identical. Analysis of (TCR) Vbeta-chain expression demonstrated increased use of superantigen-reactive Vbeta families in freshly isolated PBMC in AD patients compared with controls. This pattern of Vbeta-chain expression was only observed in the CLA+ but not the total population of T cells. Furthermore, there was a positive correlation between the enhanced PBMC proliferative response and increased expression of superantigen-reactive Vbeta families in atopic patients. These data support the concept that superantigens are important in the pathogenesis of this common condition, and also provide evidence that the increased use of certain Vbeta families in circulating, CLA+, skin homing lymphocytes is of functional significance.

Systemic PPARγ Ligation Inhibits Allergic Immune Response in the Skin

We have shown previously that specific ligands of the peroxisome proliferator-activated receptor-gamma (PPARgamma) inhibit the systemic allergic immune response. The objective of this study was to investigate the impact of PPARgamma-ligand treatment on the local allergic immune response. We established a murine model exhibiting clinical and histological features of AD-like skin lesions with high reproducibility. In this model, the PPARgamma ligand was applied in an either preventive or therapeutic manner via systemic and local routes. The affected skin areas were assessed by standardized skin score, histological analyses, and immunohistochemical examinations. Our data show that systemic application of PPARgamma ligand by a preventive protocol led to significantly reduced onset of eczematous skin lesions. This was confirmed by histology, showing decreased skin thickness accompanied by significantly reduced infiltrations of CD4+ and CD8+ lymphocytes but also mast cells. Additionally, early allergen-specific IgE and IgG1 responses were reduced (day 21/35), whereas IgG2a levels remained unchanged. In conclusion, our results demonstrate that PPARgamma-ligand treatment inhibits not only systemic allergic immune response, but also local allergen-mediated dermatitis. Our findings point to therapeutic strategies, including a PPARgamma-ligand-based treatment.

TSLP acts on infiltrating effector T cells to drive allergic skin inflammation

Thymic stromal lymphopoietin (TSLP) is a cytokine expressed by epithelial cells, including keratinocytes, and is important in allergic inflammation. Allergic skin inflammation elicited by epicutaneous immunization of mice with ovalbumin (OVA), a potential model of atopic dermatitis, was severely impaired in TSLPR(-/-) mice, as evidenced by decreased infiltration of eosinophils and decreased local expression of T helper 2 (Th2) cytokines. However, secretion of Th2 cytokines by splenocytes from epicutaneous sensitized TSLPR(-/-) mice in response to OVA was normal. Skin dendritic cells from TSLPR(-/-) mice were normal in their ability to migrate to draining lymph nodes, express activation markers, and induce proliferation and Th2 cytokine production by naïve T cells. CD4(+) T cells from TSLPR(-/-) mice expressed the skin homing receptor E-selectin ligand normally, and homed to the skin normally, but failed to transfer allergic skin inflammation to WT recipients. TSLP enhanced Th2 cytokine secretion in vitro by targeting TSLPR on antigen specific T cells. Intradermal injection of anti-TSLP blocked the development of allergic skin inflammation after cutaneous antigen challenge of OVA immunized WT mice. These findings suggest that TSLP is essential for antigen driven Th2 cytokine secretion by skin infiltrating effector T cells and could be a therapeutic target in allergic skin inflammation.

Sphingosine 1-phosphate receptor agonism impairs skin dendritic cell migration and homing to secondary lymphoid tissue: Association with prolonged allograft survival

The novel immunomodulator FTY720 is a prototypic sphingosine-1-phosphate (S1P) receptor agonist that regulates lymphocyte migration and prolongs allograft survival. Skin dendritic cells (DC) play important roles in cutaneous immunity. We investigated the migration and function of skin DC exposed to FTY720 in vivo, or to its metabolite FTY720 phosphate (P) in vitro. C57BL/10 (H2 b) recipient (but not donor) FTY720 treatment prolonged median skin C3H (H2 k) allograft survival significantly, from 12 to 34.5 days. Non-transplanted, FTY720-treated mice revealed a marked increase in skin DC, although total DC in skin-draining lymph nodes (DLN) were unchanged compared with controls. Fewer allogeneic donor DC migrated to DLN of FTY720-treated graft recipients. DC that migrated from the skin of FTY720-treated mice showed reduced MHC class II, CD86 and CCR7 expression, suggesting impaired migratory potential to secondary lymphoid tissue, that correlated with DC retention in skin, and reduced T cell stimulatory activity. Fewer DC migrated from normal skin explants exposed to the FTY720 metabolite, FTY720P than to control medium. DC that did migrate expressed lower levels of MHC class II, CD86 and CCR7, and inferior T cell stimulatory ability. These data demonstrate S1P signaling regulates skin DC trafficking and modulates MHC class II, costimulatory, and homing receptor molecule expression that impairs their ability to elicit allogeneic T cell responses.

The frequency of CLA+ CD8+ T cells in the blood of psoriasis patients correlates closely with the severity of their disease.

Psoriasis is thought to be a T cell-mediated skin disease and the cutaneous lymphocyte antigen (CLA) is an important skin homing epitope for T cells. We have studied the relationship between disease severity (PASI) and phenotypic analysis of T cells in the blood of 36 patients with psoriasis focusing on the expression of CLA, VLA-4 and CD25 on CD4+ and CD8+ T cells. The patients had a higher frequency of circulating CLA+ CD8+ cells than healthy controls. Furthermore, a much stronger correlation was observed between PASI and the frequency of CLA+ CD8+ than CLA+ CD4+ T cells. The frequency of CLA+D8+ T cells correlated more strongly with redness, thickness and scaling of the skin lesions than the total affected body surface area. In contrast to CLA the T cell expression of VLA-4 did not demonstrate any such correlation. Finally, the expression of the activation marker CD25 on CD8+ T cells showed a strong correlation with disease severity in patients with moderate to severe psoriasis (PASI > 10) but such correlation was not observed for CD4+ T cells. These findings support the notion that circulating CLA+ CD8+ T cells may play an important role in the pathogenesis of psoriasis.

Differential Gene Expression in CD4+ T Cells from Atopic Dermatitis Patients is Due to Selective Expression in the Skin Homing T Cells

MEETING ABSTRACTS: Abstracts from the Fifth Georg Rajka International Symposium of Atopic Dermatitis, Kyoto, Japan, May 11-13, 2008: Part 1: 5. Immunology of Atopy and Atopic Dermatitis

Monitoring non-immediate allergic reactions to iodine contrast media

Non-immediate reactions to iodine contrast media (ICM) affect 2-5% of patients receiving these agents. We studied the immunological mechanisms involved in patients with a confirmed non-immediate reaction, maculopapular exanthema, after administration of ICM. The diagnosis was carried out by skin testing or drug provocation test. The immunological study was performed in sequential peripheral blood mononuclear cells taken from the onset of the reaction by flow cytometry and in skin biopsy by immunohistochemistry, with specific recognition by the lymphocyte transformation test (LTT) with different ICM. Flow cytometry showed an increase in the different activation markers [CD69, CD25 and human leucocyte antigen D-related (HLA-DR)] and the skin homing receptor [cutaneous lymphocyte-associated antigen (CLA)] in CD4 lymphocytes, whereas perforin was higher in the CD8 lymphocytes. The skin biopsy showed a perivascular mononuclear infiltrate composed of CD4 lymphocytes, expressing CD25, HLA-DR and CLA, with eosinophils. Intradermal skin tests and the LTT were positive to several ICM, including the culprit agent in four and three patients, respectively, with negative results in all 10 tolerant controls. We showed that a specific immunological mechanism was implicated in patients with non-immediate reactions to ICM. Moreover, the positive results in skin tests and lymphocyte proliferation tests indicated that an important cross-reactivity exists.

TSLP is important in the effector phase of allergic skin inflammation

TSLP is a cytokine expressed by keratinocytes and is important in allergic inflammation. Allergic skin inflammation elicited by epicutaneous (EC) immunization of mice with ovalbumin (OVA), which shares many characteristics of the skin lesions of atopic dermatitis (AD), was found to be severely impaired in TSLPR−/− mice, as evidenced by decreased infiltration of eosinophils and decreased local expression of Th2 cytokines. Secretion of Th2 cytokines by splenocytes from EC sensitized mice in response to OVA was normal. Skin dendritic cells from TSLPR−/− mice were normal in their ability to migrate to draining LN, express activation markers and induce proliferation and Th2 cytokine production by naïve T cells. T cells from TSLPR−/− mice expressed the skin homing receptor E‐selectin ligand normally, and homed to the skin normally, but failed to transfer allergic skin inflammation to WT recipients. TSLP enhanced Th2 cytokine secretion by targeting TSLPR on antigen specific T cells. Intradermal injection of anti‐TSLP blocked the development of allergic skin inflammation following antigen challenge of intraperitoneally immunized WT mice. These findings suggest that TSLP is essential for antigen driven Th2 cytokine secretion by skin infiltrating T cells and could be a therapeutic target in allergic skin inflammation

Commentary 5

Studies on the pathogenesis focussing on melanocyte biology, melanin biochemistry or skin immunity have yielded a variety of hypotheses to explain the disappearance of melanocytes in vitiligo, including a genetic predisposition, increased oxidative stress and toxic metabolites, neurochemical factors and autoimmunity (1). Whereas these factors probably all contribute to the development of depigmentation (convergence theory) (2), their interaction is not clearly defined. This commentary presents a multidisciplinary view of the pathogenesis of vitiligo (Fig. 1). Schematic overview of the pathogenesis of vitiligo. Melanin synthesis in melanocytes is a tightly regulated process. Defects in the protective mechanism in the skin that scavenge radicals and toxic intermediates of melanin production may lead to vitiligo. The increased levels of oxidative stress in the vitiligo skin leads to the deactivation of catalase (3). H202 can also oxidize (6R)-l-erythro-5,6,7,8-tetrahydrobiopterin to 6-biopterin, which is cytotoxic to melanocytes. Although this melanocyte death may account for part of the depigmentation, dying melanocyte fragments will be taken up by epidermal Langerhans cells. The uptake of self-antigens from dying melanocytes in the absence of activation signals does not activate the Langerhans cells and will therefore not lead to immunity against melanocytes. Concurrent external stress factors, such as wounding, high dose of UV radiation or hormonal changes, however, activate Langerhans cells and dendritic cells in the skin, leading to breakage of tolerance (4). Clinically, these stress factors induce progression of depigmentation. The Koebner phenomenon results from stress factors at remote skin sites that induce local activation of Langerhans cells and reactivation of anti-melanocyte immunity, leading to the formation of new lesions. The lower threshold for breakage of tolerance in patients with vitiligo is illustrated by the increased incidence of autoimmune diseases in patients with vitiligo (5-12). Normally, regulatory T cells maintain peripheral tolerance by suppressing autoreactive T-cell activity. In patients with vitiligo, however, decreased levels of regulatory T cells in the skin lower the threshold for autoimmunity. Activated Langerhans cells containing melanocyte antigens migrate to the lymph nodes and present melanocyte antigenic peptides bound to HLA molecules to T cells. The association of vitiligo vulgaris with certain HLA class II alleles (13-15) indicates the dominance of peptides binding to these HLA types in inducing immunity. In the lymph nodes, melanocyte-reactive CD8+ and CD4+ T cells are activated to proliferate and migrate to the skin, resulting in increased levels of T cells reactive with tyrosinase, gp100 or MART-1 in peripheral blood (16-19), as well as autoantibodies against these antigens (20-22). Moreover, the number of circulating MART-1-reactive T cells expressing CLA in patients with vitiligo correlated with the extent of depigmentation (18). In perilesional skin, CD8+ T cells, macrophages and to a lesser extent CD4+ T cells were found (23, 24). Infiltrating CD8+ T cells expressed skin homing, cutaneous leukocyte-associated antigen (CLA) and T-cell activation markers CD25, perforin and granzyme B (25), and colocalized with disappearing melanocytes. Finally, perilesional melanocyte-reactive CD8+ cytotoxic T cells were shown to be capable of actively killing melanocytes in autologous skin tissue (J.G. van den Boorn, D. Konijnenberg, T.A.M. Dellemijn, J.P.W. van der Veen, J.D. Bos, C.J.M. Melief, F.A. Vyth-Dreese and R.M. Luiten, unpublished data). Taken together, the pathogenesis of vitiligo results from changes in biochemical processes in the skin that trigger autoimmunity, which is enhanced by genetic predisposition to autoimmunity.

Effector Function of CLA+ T Lymphocytes on Autologous Keratinocytes in Psoriasis

Background Cutaneous lymphocyte antigen (CLA) is expressed by a subgroup of memory T cells that exhibit skin homing and are implicated in cutaneous T-cell-mediated diseases. Material and methods Expression of genes associated with psoriasis was analyzed in keratinocytes taken from patients and healthy individuals and cultured under different conditions, including activation using supernatants from CLA + T lymphocytes activated with anti-CD3 and anti-CD28 antibodies. Results Keratinocytes from psoriasis patients activated by CLA + T lymphocytes expressed higher levels of interferon-inducible protein 10, HLA-DR, intercellular cell adhesion molecule 1, and inducible nitric oxide synthase. Conclusions Our results suggest that we have developed an in vitro model that will allow analysis of the effector role of CLA + T lymphocytes on keratinocytes in psoriasis. This model may allow the identification of genes involved in the pathology of psoriasis through induction by CLA + T lymphocytes.

Modulation of CLA, IL-12R, CD40L, and IL-2Rα expression and inhibition of IL-12- and IL-23-induced cytokine secretion by CNTO 1275

Cytokines interleukin (IL)-12 and IL-23 are implicated in the pathogenesis of psoriasis. IL-12 causes differentiation of CD4+ T cells to interferon-γ (IFN-γ)-producing T helper 1 (Th1) cells, while IL-23 induces differentiation to IL-17-producing pathogenic Th17 cells. The effects of the monoclonal antibody to IL-12/23 p40 subunit (CNTO 1275) on IL-12 receptor (IL-12R) expression, markers associated with skin homing, activation, and cytokine secretion were investigated in vitro using human peripheral blood mononuclear cells (PBMCs) from healthy donors. PBMCs were activated in the presence or absence of recombinant human (rh) IL-12 or rhIL-23, with or without CNTO 1275. CNTO 1275 inhibited upregulation of CLA, IL-12R, IL-2Rα and CD40L expression and also inhibited IL-12- and IL-23-induced IFN-γ, IL-17A, tumor necrosis factor (TNF)-α, IL-2, and IL-10 secretion. Thus, the therapeutic effect of CNTO 1275 may be attributed to the IL-12/23 neutralization, resulting in decreased expression of skin homing and activation markers, and IL-12- and IL-23-induced cytokine secretion.

Human skin migratory dendritic cells that do not secrete IL-12p70 stimulate both Th17 and Th1 allogeneic responses (36.20)

Abstract We analyzed the ability of human skin migratory dendritic cells (smiDC) to stimulate allogeneic (allo)-CD4+ T helper cell responses and to induce differentiation of Th1 and Th17 cells. SmiDCs obtained from cultures of human skin explants consisted of Langerhans cells and dermal DCs, which synthesized IL-8, IL-15, IL-23, IL-10 and TGF-β1, but not IL-12p70, even after exposure to DC1-driving stimuli. Regardless of the lack of IL-12p70 smiLC and DDC induced differentiation of effector memory Th cells that expressed CD45RO, the skin homing molecule CLA, and decreased CD62L and CCR7. SmiDCs stimulated proliferation of allo-CD4+ T cells that differentiated into Th1 and Th17 cells during 5 day-MLCs. T cell proliferation depended on the expression of MHC-II, costimulatory and adhesion molecules by smiDCs. The Th1 biasing function of smiDCs depended on the production of IL-23. The Th17 response was supported by the proinflammatory cytokines IL-8 and IL-15 and was significantly increased by the blockade of IL-6, whereas the blockade of IL-23 did not affect the secretion of IL-17. Levels of IL-17 and IFN-γ secretion reached their maximum at day 4 and 5, respectively. IFN-γ (Th1) and IL-17 (Th17) was produced by two distinct Th cell subsets as demonstrated by flow cytometry. Therefore, human smiDCs support the induction and coexistence of Th1 and Th17 effector T cells by mechanisms distinct from those described in the mouse model.