Effector and regulatory mechanisms in allergic contact dermatitis

Allergic contact dermatitis (ACD), one of the commonest occupational diseases, is a T-cell-mediated skin inflammation caused by repeated skin exposure to contact allergens, i.e. nonprotein chemicals called haptens. Allergic contact dermatitis, also referred to as contact hypersensitivity, is mediated by CD8+ T cells, which are primed in lymphoid organs during the sensitization phase and are recruited in the skin upon re-exposure to the hapten. Subsets of CD4+ T cells endowed with suppressive activity are responsible for both the down-regulation of eczema in allergic patients and the prevention of priming to haptens in nonallergic individuals. Therefore, ACD should be considered as a breakdown of the skin immune tolerance to haptens. Recent advances in the pathophysiology of ACD have demonstrated the important role of skin innate immunity in the sensitization process and have revisited the dogma that Langerhans cells are mandatory for CD8+ T-cell priming. They have also introduced mast cells as a pivotal actor in the magnitude of the inflammatory reaction. Finally, the most recent studies address the nature, the mode and the site of action of the regulatory T cells that control the skin inflammation with the aim of developing new strategies of tolerance induction in allergic patients.     

CD4+CD25+ regulatory T cells utilize FasL as a mechanism to restrict DC priming functions in cutaneous immune responses

Recent studies have suggested Fas‐mediated elimination of antigen‐presenting cells as an important mechanism down‐regulating the induction of autoimmune responses. It remains unknown whether this mechanism restricts the magnitude of immune responses to non‐self antigens. We used a mouse model of a cutaneous CD8⁺ T‐cell‐mediated immune response (contact hypersensitivity, CHS) to test if CD4⁺CD25⁺ T cells expressing FasL regulate hapten‐specific effector CD8⁺ T cell expansion through the elimination of Fas‐expressing hapten‐presenting DC. In WT mice, attenuation of CD4⁺CD25⁺ T regulatory cell activity by anti‐CD25 mAb increased hapten‐presenting DC numbers in skin‐draining LN, which led to increased effector CD8⁺ T‐cell priming for CHS responses. In contrast, CD4⁺CD25⁺ T cells did not regulate hapten‐specific CD8⁺ T‐cell priming and CHS responses initiated by Fas‐defective (lpr) DC. Thus, restricting DC priming functions through Fas–FasL interactions is a potent mechanism employed by CD4⁺CD25⁺ regulatory cells to restrict CD8⁺ T‐cell‐mediated allergic immune responses in the skin.     

Regulatory role of CD4+ T cells during the development of contact hypersensitivity responses

Contac thypersensitivity (CHS) is a T cell-mediated immune response to cutaneous sensitization and subsequent challenge with haptens such as dinitrofluorobenzene and oxazolone. Many aspects concerning the development and regulation of CHS remain unknown. Using CHS as a model of T cell-mediated immune responses to antigens deposited in the skin we have studied the development and function of effector and regulatory T cell componenets of this response. These studies have revealed the effector role of hapten-specific CD8⁺ T cells in this response. In contrast, hapten-specific CD4⁺ T cells negatively regulate the magnitude and duration of the response. In this article we propose a model in which the CD4⁺ T cells during sensitization for CHS and discuss potential mechanisms that CD4⁺ T cells might utilize to mediate this regulation.     

Diversion of CD4+ T cell development from regulatory T helper to effector T helper cells alters the contact hypersensitivity response

Cutaneous sensitization to reactive haptens and subsequent challenge results in a T cell-mediated response, contact hypersensitivity (CHS). Recent results from this laboratory have indicated that hapten sensitization induces two populations of reactive T cells: CD8⁺ T cells producing interferon (IFN)-γ which mediate the response and CD4⁺ T cells producing interleukin (IL)-4 and IL-10 which negatively regulate the magnitude and duration of the response. Since CD4⁺ T cell development to either IFN-γ- (Th1) or IL-4/IL-10- (Th2)-producing cells is dependent upon the cytokine environment during antigen priming, we hypothesized that CD4⁺ T cell induction in a Th1-promoting environment would not only alter the CD4⁺ T cell cytokine-producing phenotype but also the course of the CHS response. Administration of the Th1-promoting cytokine IL-12 during hapten sensitization resulted in a CHS response of greater magnitude following challenge and extended the duration of the response. In hapten-sensitized mice depleted of CD8⁺ T cells, treatment with IL-12 induced effector CD4⁺ T cells. Histological examination of challenged ear tissue from these mice indicated minimal edema and an acute mononuclear cell infiltration more typical of classical delayed-type hypersensitivity than CHS. Hapten-primed CD4⁺ T cells from IL-12 treated, sensitized mice produced IFN-γ, but not IL-4 in response to T cell receptor-mediated stimulation. Use of neutralizing anti-IFN-γ antibody indicated that IL-12 not only directly promoted Th1 development but also indirectly inhibited Th2 development through stimulation of IFN-γ production at the time of hapten sensitization. Overall, these results demonstrate that diversion of CD4⁺ T cell development to Th1 effector cells rather than to Th2 cells alters the efferent nature of CHS and removes a primary regulatory mechanism of the immune response.     

Major histocompatibility complex class I-restricted CD8+ T cells and class II-restricted CD4+ T cells,respectively, mediate and regulate contact sensitivity to dinitrofluorobenzene

Contact sensitivity (CS) is a form of delayed-type hypersensitivity to haptens applied epicutaneously and is thought to be mediated, like classical delayed-type hypersensitivity responses, by CD4⁺ T helper-1 cells. The aim of this study was to identify the effector T cells involved in CS. We studied CS to the strongly sensitizing hapten dinitrofluorobenzene (DNFB) in mice rendered deficient by homologous recombination in either major histocompatibility complex (MHC) class I, MHC class II, or both, and which exhibited deficiencies in, respectively, CD8⁺, CD4⁺, or both, T cells. MHC class I single-deficient and MHC class I/class II double-deficient mice, both of which have a drastic reduction in the number of CD8⁺ T cells, were unable to mount a CS response to DNFB. In contrast, both MHC class II-deficient mice and normal mice treated with an anti-CD4 monoclonal antibody (mAb) developed exaggerated and persistent responses relative to heterozygous control littermates. Furthermore, anti-CD8 mAb depletion of class II-deficient mice totally abolished their ability to mount an inflammatory response to DNFB. Removal of residual CD4⁺ T cells in class II-deficient mice by anti-CD4 mAb treatment did not diminish the intensity of CS. These data clearly demonstrate that class I-restricted CD8⁺ T cells are sufficient for the induction of CS to DNFB, and further support the idea that MHC class II-restricted CD4⁺ T cells down-regulate this inflammatory response.     

Induction and regulation of T-cell priming for contact hypersensitivity

Contact hypersensitivity (CHS) is a T-cell-mediated immune response to cutaneous sensitization and subsequent challenge with haptens such as dinitrofluorobenzene and oxazolone. Clinically, contact sensitivity, also called allergic contact dermatitis, is a frequently observed dermatosis in industrialized countries. Experimental CHS in mice has been used by many laboratories as a model of T-cell-mediated immune responses to antigens deposited onto the skin to study the priming, development, and function of effector and regulatory T-cell components during these responses. In this article we discuss the mechanism of T-cell priming by hapten-presenting Langerhans cells and how the priming environment influences the development of these hapten-specific T cells to different functional phenotypes during sensitization for the CHS response. Finally, we propose a model of negative regulation of the CHS response by T-cell components that are coincidentally primed with the effector T cells mediating the response. Overall, these aspects indicate a unique immune response mediated and regulated by specialized antigen-presenting cells and T-cell populations.     

Depletion of CD4+CD25+ T cells switches the whey‐allergic response from immunoglobulin E‐ to immunoglobulin free light chain‐dependent

Background Symptoms of allergy are largely attributed to an IgE‐mediated hypersensitivity response. However, a considerable number of patients also exhibit clinical features of allergy without detectable systemic IgE. Previous work showed that Ig‐free light chains (IgLC) may act as an alternate mechanism to induce allergic responses. CD4⁺CD25⁺ T cells are crucial in the initiation and regulation of allergic responses and compromised function might affect the response to allergens. Objective To examine the contribution of CD4⁺CD25⁺ T cells and IgLC towards the whey‐allergic response. Methods Mice were sensitized orally with whey using cholera toxin as an adjuvant. CD25⁺ T cells were depleted in vivo using a CD25 mAb. The acute allergic skin response to whey and ex vivo colon reactivity was measured in the presence or absence of F991, a specific inhibitor of IgLC. Serum whey‐specific antibodies and IgLC in serum and mesenteric lymph node (MLN) supernatants were measured. Depletion of CD4⁺CD25⁺ T cells was confirmed in the spleen. Results Anti‐CD25 treatment strongly reduced whey‐specific antibody levels and resulted in a partial depletion of effector T cells and a major depletion of Foxp3⁺ regulatory T cells. Surprisingly, despite the abolished specific IgE response, the acute allergic skin response to whey was not affected. IgLC levels were enhanced in the serum and MLN supernatants of CD25‐depleted sensitized mice. F991 inhibited the acute skin response and colon hyperreactivity in anti‐CD25‐treated mice, indicating that these responses were mainly IgLC dependent. Conclusions Depletion of CD4⁺CD25⁺ T cells resulted in a switch from an IgE‐ to an IgLC‐dependent acute skin response and functional hyperresponsiveness of the colon. Our data suggest that CD25⁺ T cells play a crucial role in balancing cow's milk allergy between IgE and IgE‐independent responses and both mechanisms might play a role in allergic responses to the same allergen. Cite this as: B. C. A. M. van Esch, B. Schouten, B. R. J. Blokhuis, G. A. Hofman, L. Boon, J. Garssen L. M. J. Knippels, L. E. M. Willemsen and F. A. Redegeld, Clinical & Experimental Allergy, 2010 (40) 1414–1421.     

Lactobacillus casei reduces CD8+ T cell-mediated skin inflammation

Probiotics, including Lactobacilli, have been postulated to alleviate allergic and inflammatory diseases, but evidence that they exert an anti-inflammatory effect by immune modulation of pathogenic T cell effectors is still lacking. The aim of this study was to examine whether L. casei could affect antigen-specific T cell-mediated skin inflammation. To this end, we used contact hypersensitivity to the hapten 2,4-dinitrofluorobenzene, a model of allergic contact dermatitis mediated by CD8+ CTL and controlled by CD4+ regulatory T cells. Daily oral administration of fermented milk containing L. casei or L. casei alone decreased skin inflammation by inhibiting the priming/expansion of hapten-specific IFN-gamma-producing CD8+ effector T cells. The down-regulatory effect of the probiotics required the presence of CD4+ T cells, which control the size of the hapten-specific CD8+ T cell pool primed by skin sensitization. L. casei cell wall was as efficient as live L. casei to regulate both the CHS response and the hapten-specific CD8+ T cell response, suggesting that cell wall components contribute to the immunomodulatory effect of L. casei. This study provides the first evidence that oral administration of L. casei can reduce antigen-specific skin inflammation by controlling the size of the CD8+ effector pool.     

Systemic immunogenicity of para-Phenylenediamine and Diphenylcyclopropenone: two potent contact allergy-inducing haptens

p-Phenylenediamine (PPD) and Diphenylcyclopropenone (DPCP) are two potent haptens. Both haptens are known to cause delayed-type hypersensitivity, involving a cytokine response and local infiltration of T-cell subpopulations, resulting in contact dermatitis. We investigated the systemic immune effects of PPD and DPCP, two relatively unexplored skin allergens. The dorsal sides of the ears of BALB/c mice were exposed to PPD or DPCP (0.1 % w/v or 0.01 % w/v), or vehicle alone. Mice were treated once daily for 3 days (induction period) and subsequently twice per week for 8 weeks. Local and systemic immune responses in the auricular and pancreatic lymph nodes, spleen, liver, serum, and ears were analyzed with cytokine profiling MSD, flow cytometry, and qPCR. Ear swelling increased significantly in mice treated with 1 % PPD, 0.01 % DPCP or 0.1 % DPCP, compared with vehicle treatment, indicating that the mice were sensitized and that there was a local inflammation. Auricular lymph nodes, pancreatic lymph nodes, spleen, and liver showed changes in regulatory T-cell, B-cell, and NKT-cell frequencies, and increased activation of CD8⁺ T cells and B cells. Intracellular cytokine profiling revealed an increase in the IFN-γ- and IL-4-positive NKT cells present in the liver following treatment with both haptens. Moreover, we saw a tendency toward a systemic increase in IL-17A. We observed systemic immunological effects of PPD and DPCP. Furthermore, concentrations too low to increase ear thickness and cause clinical symptoms may still prime the immune system. These systemic immunological effects may potentially predispose individuals to certain diseases.     

Insufficient CD100 shedding contributes to suppression of CD8+ T-cell activity in non-small cell lung cancer

CD100 is an immune semaphorin constitutively expressed on T-cells. Matrix metalloproteinase (MMP) is an important mediator of membrane-bound CD100 (mCD100) cleavage to generate soluble CD100 (sCD100), which has immunoregulatory activity in immune cell responses. The aim of the study was to investigate the level and role of sCD100 and mCD100 in modulating CD8⁺ T-cell function in non-small cell lung cancer (NSCLC). sCD100 and MMP-14 levels in the serum and bronchoalveolar lavage fluid (BALF), and mCD100 expression on peripheral and lung-resident CD8⁺ T-cells were analysed in NSCLC patients. The ability to induce sCD100 and the effect of MMP-14 on mCD100 shedding for the regulation of non-cytolytic and cytolytic functions of CD8⁺ T-cells were also analysed in direct and indirect contact co-culture systems. NSCLC patients had lower serum sCD100 and higher mCD100 levels on CD8⁺ T-cells compared with healthy controls. BALF from the tumour site also had decreased sCD100 and increased mCD100 on CD8⁺ T-cells compared with the non-tumour site. Recombinant CD100 stimulation enhanced non-cytolytic and cytolytic functions of CD8⁺ T-cells from NSCLC patients, whereas blockade of CD100 receptor CD72 attenuated CD8⁺ T-cell activity. NSCLC patients had lower MMP-14 in the serum and in BALF from the tumour site. Recombinant MMP-14 mediated mCD100 shedding from CD8⁺ T-cell membrane, and led to promotion of CD8⁺ T-cell response in NSCLC patients. Overall, decreased MMP-14 resulted in insufficient CD100 shedding, leading to suppression of peripheral and lung-resident CD8⁺ T-cell activity in NSCLC.     

A novel peptide vaccination augments cytotoxic CD8+ T-cell responses against Mycobacterium tuberculosis HspX antigen

Cellular immunity is a critical factor determining the safety and efficacy of newly developed vaccines against Mycobacterium tuberculosis infection. Crosstalk between CD4⁺ and CD8⁺ T-lymphocytes plays central roles in perpetuating the cytotoxic killing to the infected cells for host clearance. Our study proposed a novel alternating MHC-class II restricted peptide vaccination strategy to enhance the antigen-specific CD8⁺ T-cell activity against alpha-crystalline heat-shock protein (HspX) in C57BL/6 mice. Alternating peptide vaccination significantly stimulated a prominent HspX-specific CD8⁺ T-cell response with elevated Th1 and Th17 responses, without interference from Tregs suppression. Heightened central and effector CD8 memory were apparent in mice receiving alternating peptide vaccine, indicating a persisting recall immunity against HspX antigen. It was unlikely for alternating peptide vaccine to cause dysregulation in CD8⁺ T-cells as shown by minimal expression of KLRG1, PD1, LAG3, and CTLA-4 markers. Strong cytotoxic T-lymphocyte (CTL) responses were demonstrated in mice administrated with alternating peptide vaccines, suggesting its capacity in executing killing effector function against targeted cells. In conclusion, our novel vaccination strategy delineated potential benefits of alternating MHC-II peptides to invigorate efficient cytotoxic CD8⁺ T-cell responses against HspX antigen. Such approach might be applicable to serve as alternative immunotherapy for latent tuberculosis infection in future.     

The murine buccal mucosa is an inductive site for priming class I-restricted CD8+ effector T cells in vivo

The present study shows that Langerhans cells of the buccal mucosa and the skin share a similar phenotype, including in situ expression of MHC class II, the mannose receptor DEC-205 and CD11c, and absence of the costimulatory molecules B7.1, B7.2 and CD40 as well as Fas. Application of 2,4-dinitrofluorobenzene (DNFB) onto the buccal mucosa is associated with a rapid migration of dendritic cells (DC) to the epithelium and induction of B7.2 expression on some DC. Buccal sensitization with DNFB elicited a specific contact sensitivity (CS) in response to skin challenge, mediated by class I-restricted CD8⁺ effector T cells and down-regulated by class II-restricted CD4⁺ T cells, demonstrated by the lack of priming of class I-deficient mice and the enhanced response of class II-deficient mice, respectively. CS induced by buccal immunization is associated with priming of class I-restricted CD8⁺ effector T cells endowed with hapten-specific cytotoxic activity. Thus, the buccal epithelium is an inductive site, equivalent to the epidermis, for the generation of CS independent of CD4 help, and of cytotoxic T lymphocyte (CTL) responses mediated by class I-restricted CD8⁺ T cells. We propose that immunization through the buccal mucosa, which allows antigen presentation by epithelial DC efficient for priming systemic class I-restricted CD8⁺ CTL, may be a valuable approach for single-dose mucosal vaccination with subunit vaccines.     

Systemic low-dose UVB inhibits CD8 T cells and skin inflammation by alternative and novel mechanisms

Exposure to UVB radiation before antigen delivery at an unirradiated site inhibits functional immunological responses. Mice treated dorsally with suberythemal low-dose UVB and immunized with ova in abdominal skin generated ova-specific CD8 T cells with a significantly decreased activation, expansion, and cytotoxic activity compared with unirradiated mice. UVB also impaired the delayed-type hypersensitivity (DTH) reaction to ova. Transfer of CD4⁺CD25⁺ cells from UVB-exposed mice did not suppress the ova-specific CD8 T-cell response or DTH reaction in unexposed mice, confirming that systemic low-dose UVB does not induce long-lived functional regulatory CD4⁺CD25⁺ T cells. Repairing cyclobutane pyrimidine dimer–type DNA damage and blocking aryl hydrocarbon receptor signaling also did not reverse the immunosuppressive effect of UVB on ova-specific CD8 T cells and DTH, suggesting that cyclobutane pyrimidine dimers and the aryl hydrocarbon receptor are not required in systemic low-dose UVB-induced immunosuppression. The known UVB chromophore, cis-urocanic acid, and reactive oxygen species triggered the inhibition of DTH caused by UVB, but they were not involved in the modulation of CD8 T cells. These findings indicate that systemic low-dose UVB impedes the primary response of antigen-specific CD8 T cells by a novel mechanism that is independent of pathways known to be involved in systemic suppression of DTH.UVB radiation (290 to 320 nm) in natural sunlight is a potent immunosuppressant. UVB can inhibit the immune system from generating optimal responses to tumors, contact haptens, and various microbial antigens (Ags; viral, fungal, and parasitic) that can lead to exacerbated disease. Alternatively, immunosuppressive UVB can also be beneficial to control autoimmune diseases, such as psoriasis¹ and experimental autoimmune encephalomyelitis.² The epidermis of skin absorbs UVB through chromophores, including nuclear DNA, cytoplasmic tryptophan, and extracellular trans-urocanic acid (UCA). The molecular processes that follow trigger a cascade of events that cumulates in the phenomenon of UVB-induced immunosuppression. Some of the hallmarks of this immunosuppression include UVB-induced genetic mutations in skin cells, circulation of cis-UCA from the isomerization of trans-UCA, production of reactive oxygen species (ROS), and generation of regulatory T and B cells that can transfer suppression into UVB-naïve mice.³ Because UVB has both detrimental and beneficial effects on the immune system, it is critical to understand the mechanisms regulated by UVB so that effective prophylactic and palliative therapies can be designed for skin diseases, such as skin cancer, and immune-mediated diseases in internal organs, such as multiple sclerosis.A previous study⁴ showed that UVB can inhibit CD8 and CD4 T-cell responses to haptens. In a model of contact hypersensitivity (CHS), we demonstrated that a low dose of UVB (approximately 5 minutes of summer sunlight in Sydney, Australia, at midday) is sufficient to inhibit the activation and expansion of effector CD8 and CD4 T cells in skin-draining lymph nodes (sDLNs) after sensitization to a contact hapten at an unirradiated site (systemic, Ag, and UVB at distal sites). However, it was too low to activate functional and durable CD4⁺CD25⁺ regulatory T cells. The effector T cells generated in this environment exhibited reduced skin infiltration and interferon-γ production on CHS elicitation. Moreover, this systemic low-dose UVB regimen prevented the development of dermal memory CD8 T cells.Exposing mice to a low-dose UVB regimen, followed by transcutaneous immunization with ova protein through the same skin site (local, Ag, and UVB at the same site), inhibits the proliferation, cytotoxicity, and interferon-γ production of transgenic and endogenous ova-specific CD8 T cells.^5,6 Contrary to what we previously observed, transferable suppression of the ova-specific CD8 T-cell response was correlated to the presence of CD4⁺CD25⁺ regulatory T cells in sDLNs in this model.⁵ Other researchers^7,8 have also demonstrated that regulatory T cells derived from mice irradiated with inflammatory high doses of UVB in a systemic Ag model can impede CHS and delayed-type hypersensitivity (DTH) reactions. These UV-activated regulatory T cells may inhibit T cells and skin inflammatory reactions by altering Ag-presenting cells (APCs).⁹Several UVB chromophores have been identified that can independently trigger UVB-induced immunosuppression, as shown by various studies that have repaired DNA damage, neutralized cis-UCA, and prevented ROS production. The downstream processes initiated by UVB chromophores include production of immunosuppressive mediators [ie, IL-4, IL-10, and platelet-activating factor (PGE₂)], migration of skin APCs into sDLNs, aberrant Ag presentation, mast cell activation, and induction of regulatory T cells.¹⁰ However, it is unknown whether these pathways are involved during systemic low-dose UVB, which is representative of daily nonrecreational sunlight exposure. Given that a previous investigation showed that UVB has a long-term deleterious influence on CD8 T-cell immunity, we wanted to further examine what UVB-stimulated mechanisms contribute to the inhibition of primary CD8 T-cell responses in the absence of CD4⁺CD25⁺ regulatory T cells. In addition, we assessed the ability of systemic low-dose UVB to modulate a second separate inflammatory reaction in the skin at an unirradiated site. DTH reactions are complex skin immune reactions that are primarily driven by type 1 helper CD4 T cells and various innate cells.^11,12 For this study, we used the model protein Ag, ova, that allowed us to study the endogenous Ag-specific CD8 T-cell response and a DTH reaction after UVB irradiation and immunization. UVB significantly decreased the activation, expansion, and cytotoxic activity of splenic ova-specific CD8 T cells, but this was not attributed to known UVB chromophores considered to be critical in UVB-induced immunosuppression. However, DTH reactions were modulated by cis-UCA and ROS. These findings indicate that short-term UVB can inhibit Ag-specific CD8 T-cell responses and DTH in vivo via different mechanisms and, therefore, that a novel unknown mechanism is responsible for regulating the effects of UVB on CD8 T-cell activation in secondary lymphoid organs.     

Antigen-specific cytotoxic T lymphocytes target airway CD103+ and CD11b+ dendritic cells to suppress allergic inflammation

Allergic airway inflammation is driven by the recognition of inhaled allergen by T helper type 2 (Th2) cells in the airway and lung. Allergen-specific cytotoxic T lymphocytes (CTLs) can strongly reduce airway inflammation, however, the mechanism of their inhibitory activity is not fully defined. We used mouse models to show that allergen-specific CTLs reduced early cytokine production by Th2 cells in lung, and their subsequent accumulation and production of interleukin (IL)-4 and IL-13. In addition, treatment with specific CTLs also increased the proportion of caspase⁺ dendritic cells (DCs) in mediastinal lymph node (MLN), and decreased the numbers of CD103⁺ and CD11b⁺ DCs in the lung. This decrease required expression of the cytotoxic mediator perforin in CTLs and of the appropriate MHC-antigen ligand on DCs, suggesting that direct CTL-DC contact was necessary. Lastly, lung imaging experiments revealed that in airway-challenged mice XCR1-GFP⁺ DCs, corresponding to the CD103⁺ DC subset, and XCR1-GFP⁻ CD11c⁺ cells, which include CD11b⁺ DCs and alveolar macrophages, both clustered in the areas surrounding the small airways and were closely associated with allergen-specific CTLs. Thus, allergen-specific CTLs reduce allergic airway inflammation by depleting CD103⁺ and CD11b⁺ DC populations in the lung, and may constitute a mechanism through which allergic immune responses are regulated.     

Increased CCL27-CCR10 expression in allergic contact dermatitis: implications for local skin memory

Allergic contact dermatitis (ACD) is a T-cell-mediated disease in which expression of a distinct repertoire of chemokines results in the recruitment of effector T cells into the skin. While it is becoming clear which chemokines and receptors determine the development of ACD, the mechanisms involved in the retention of T cells in the skin after resolution of inflammation are still unknown. Unravelling these mechanisms will help us to understand local skin memory as observed in retest reactivity and flare-up reactions. This study was designed to evaluate the role of chemokine-chemokine receptor interactions in local T-cell retention. The results show that expression of the CCR10 targeting ligand CCL27 is not only increased during inflammation, but also remains increased several weeks after clinical responsiveness to patch testing. In parallel with increased CCL27 expression, an increased number of infiltrating cells could still be detected in skin that, clinically, had returned to normal 21 days after patch testing. These persisting cells were characterized as CD4+ cells expressing CCR10, while no CD8+ CCR10+ cells could be detected. The presence of these cells is most likely an allergen-mediated effect, as increased levels of CCL27 and CCR10 could not be detected 21 days after initiating an irritant contact dermatitis reaction. In contrast to CCL27, increased expression of CXCL9, CXCL10, and CXCL11 could only be observed during the clinically inflammatory phase of ACD. In conclusion, local CCL27-mediated retention of CCR10+ CD4+ T cells in sites previously challenged by ACD could be responsible for phenomena such as local skin memory observed in retest reactions and flare-up reactions in which the presence of persisting T cells results in an accelerated inflammatory response upon renewed allergen challenge.     

UV inhibits allergic airways disease in mice by reducing effector CD4+ T cells

Background In human asthma, and experimental allergic airways disease in mice, antigen‐presenting cells and CD4⁺ effector cells at the airway mucosa orchestrate, and CD4⁺CD25⁺ regulatory T cells attenuate, allergen immunity. UV irradiation of skin before sensitization with ovalbumin (OVA) causes significantly reduced asthma‐like responses in respiratory tissues. Objective To determine whether UV‐induced changes in CD11c⁺ cells, CD4⁺CD25⁺ effector cells or CD4⁺CD25⁺ regulatory cells in the trachea and airway draining lymph nodes (ADLNs) were responsible for reduced allergic airways disease. Methods The phenotype and function of CD11c⁺ cells and CD4⁺CD25⁺ cells in the trachea and ADLNs of UV‐ and non‐irradiated, OVA‐sensitized mice was examined 24 h after a single exposure to aerosolized OVA. Results No changes in the function of CD11c⁺ cells from UV‐irradiated mice were observed. CD4⁺CD25⁺ cells from UV‐irradiated, OVA‐sensitized mice harvested 24 h after OVA aerosol proliferated less in response to OVA in vitro and were unable to suppress the proliferation of OVA‐sensitized responder cells. This result suggested reduced activation of effector T cells in the airway mucosa of UV‐irradiated, OVA‐sensitized mice. To exclude regulatory cells of any type, there was similar proliferation in vivo to aerosolized OVA by CFSE‐loaded, OVA‐TCR‐specific CD4⁺ cells adoptively transferred into UV‐ and non‐irradiated, OVA‐sensitized mice. In addition, there was no difference in the expression of regulatory T cell markers (Foxp3, IL‐10, TGF‐β mRNA). To examine effector T cells, ADLN cells from UV‐irradiated, OVA‐sensitized and ‐challenged mice were cultured with OVA. There was reduced expression of the early activation marker CD69 by CD4⁺CD25⁺ cells, and reduced proliferation in the absence of the regulatory cytokine, IL‐10. Conclusion Reduced allergic airways disease in UV‐irradiated mice is due to fewer effector CD4⁺CD25⁺ cells in the trachea and ADLNs, and not due to UV‐induced regulatory cells. Cite this as: J. P. McGlade, D. H. Strickland, M. J. M. Lambert, S. Gorman, J. A. Thomas, M. A. Judge, J. T. Burchell, G. R. Zosky and P. H. Hart, Clinical & Experimental Allergy, 2010 (40) 772–785.     

Regulators of Glucose Metabolism in CD4+ and CD8+ T Cells

Much like cancer cells, activated T cells undergo various metabolic changes that allow them to grow and proliferate rapidly. By adopting aerobic glycolysis upon activation, T cells effectively prioritize efficiency in biosynthesis over energy generation. There are distinct differences in the way CD4⁺ and CD8⁺ T cells process activation signals. CD8⁺ effector T cells are less dependent on Glut1 and oxygen levels compared to their CD4⁺ counterparts. Similarly the downstream signaling by TCR also differs in both effector T cell types. Recent studies have explored PI3K/Akt, mTORC, HIF1α, p70S6K and Bcl-6 signaling in depth providing definition of the crucial roles of these regulators in glucose metabolism. These new insights may allow improved therapeutic manipulation against inflammatory conditions that are associated with dysfunctional T-cell metabolism such as autoimmune disorders, metabolic syndrome, HIV, and cancers.     

Antigen processing and CD24 expression determine antigen presentation by splenic CD4+ and CD8+ dendritic cells

To examine heterogeneity in dendritic cell (DC) antigen presentation function, murine splenic DCs were separated into CD4⁺ and CD8⁺ populations and assessed for the ability to process and present particulate antigen to CD4⁺ and CD8⁺ T cells. CD4⁺ and CD8⁺ DCs both processed exogenous particulate antigen, but CD8⁺ DCs were much more efficient than CD4⁺ DCs for both major histocompatibility complex (MHC) class II antigen presentation and MHC class I cross-presentation. While antigen processing efficiency contributed to the superior antigen presentation function of CD8⁺ DCs, our studies also revealed an important contribution of CD24. CD8⁺ DCs were also more efficient than CD4⁺ DCs in inducing naïve T cells to acquire certain effector T-cell functions, for example generation of cytotoxic CD8⁺ T cells and interferon (IFN)-γ-producing CD4⁺ T cells. In summary, CD8⁺ DCs are particularly potent antigen-presenting cells that express critical costimulators and efficiently process exogenous antigen for presentation by both MHC class I and II molecules.