Extravascular T-cell recruitment requires initiation begun by Vα14+ NKT cells and B-1 B cells

doi:10.1016/j.it.2004.06.003

Trends in Immunology

Volume 25, Issue 8, 1 August 2004, Pages 441-449

https://doi.org/10.1016/j.it.2004.06.003 Get rights and content

Abstract

Contact sensitivity and delayed hypersensitivity are principal in vivo models for recruitment of effector T cells into tissues. New data suggest that T-cell recruitment depends on an early antigen-specific ‘initiation process’. To begin, glycolipids released following skin immunization induce Vα14⁺ invariant natural killer T cells in the liver to produce interleukin-4, which, together with dispersed antigen, coactivates specific peritoneal B-1 B cells to produce circulating antigen-specific IgM antibodies within just one day. At elicitation, these antibodies form complexes with the antigen, thereby activating complement locally, generating C5a; this acts on local mast cells and platelets to release vasoactive serotonin and tumor necrosis factor-α, leading to T-cell recruitment. Similar ‘initiation processes’ probably mediate the recruitment of effector T cells in autoimmunity, asthma, infections and cancers.

Section snippets

New view of the elicitation of CS and DTH

For CS responses, mice are immunized on day 0 by skin painting with a reactive hapten Ag, such as 2,4,6-trinitrophenyl, on the body and paws. Subsequently, the ears are challenged with dilute hapten, eliciting ‘hypersensitive’ ear-swelling reactions, which can be measured with a micrometer. Ear biopsies are used to determine histology and cytokine and chemokine content. In mice with gene defects that result in deficient CS responses, we can reconstitute the defective responses by transfer of

Elicitation of CS and DTH responses

Determining the induction events leading to the activation of B-1 cells uncovered a novel role for natural killer T (NKT) cells [24]. The principal subset of NKT cells expresses T-cell receptors (TCR) with the invariant rearrangement Vα14 Jα18. These Vα14i NKT cells respond to exogenous and endogenous glycolipid Ag in association with the MHC class I-like molecule CD1d on APCs, resulting in strong and rapid cytokine production 25, 26, and are normally activated to express cytokine mRNA [27],

The core of the initiation process

An essential finding is that sensitized circulating T cells are not sufficient to mediate either CS or DTH responses following Ag challenge; Ag-specific antibodies are required for elicitation of these responses. This was first shown in an experiment to test whether a local antibody reaction could recruit T cells. We determined that Ag-specific IgE-mediated release of vasoactive mediators from mast cells resulted in the recruitment of effector T cells [30]. Thus, donor populations containing

Induction of the initiating process

Actively immunized iNKT cell-deficient mice (Jα18^−/−, CD1d^−/−) fail to elicit CS responses despite the presence of sensitized and circulating effector T cells [24]. This suggests a defect in the initiating phase of the effector limb. Indeed, CS responses are restored by transferring wild-type liver mononuclear cells (LMNC) containing normal Vα14i NKT cells (35% of the T-cell population), but not by LMNC from IL-4^−/− mice, or by LMNC from Jα18^−/− mice deficient in iNKT cells [24] (Figure 4).

Detection of T-cell recruitment

How can recruitment of T cells be determined early after elicitation of the responses? Previous dose–response local transfer studies using cloned DTH-effector T cells with Ag, showed that just one single T cell was sufficient for DTH elicitation [45]. Thus, current technologies preclude determination of the actual onset of extravascular T-cell recruitment. However, the initiation process appears to proceed rapidly, within two hours after Ag challenge. This was determined by skin swelling

Alternative initiating components and other initiating pathways

Redundancy of mechanisms is recognized in important biological pathways, causing complexity in the system. CS and DTH-initiation processes are complex (Figure 1, Figure 2). Accordingly, our studies suggest that other initiating pathways can exist. For example, in mouse strains with deficient components in the two-hour initiating phase, the 24-hour phase is not absent but is significantly reduced; such strains include Jα18^−/−, CD1d^−/−, JH^−/−, μMT (B-cell deficient), xid, C5^−/− and mast

Possible initiation of T-cell recruitment in other systems

The initiation process occurs in a variety of CS and DTH models (Box 1). The various components participating in the initiation of T-cell recruitment (i.e. iNKT cells, B cells, antibodies, complement and mast cells) have been shown to play an important role in several disease models mediated by effector T cells. This includes Th2 models of asthma 38, 39, 55, collagen arthritis mimicking rheumatoid arthritis [56], and other Th1 autoimmune diseases, including: encephalomyelitis and multiple

CD8 Tc1 responses and initiation

Our data show that, besides the need for initiation in CD4⁺ Th1-mediated CS and DTH, responses mediated by CD8⁺ Tc1 cells also require this process 3, 15, 32. Thus, initiation of extravascular T-cell recruitment is probably essential in Tc1-mediated tumor immunity and in resistance to some infections mediated by CD8⁺ cytotoxic cells. An active two-hour initiating phase present in one-day immune mice is required for recruiting effector T cells in resistance to murine ultraviolet-induced

Clinical implications of differing Ag specificities of initiation versus effector phases

The Ag specificity of the required early phase need not be the same as that required in the late T-cell phase 7, 31. This ‘dual Ag effect’ could mean that the onset or exacerbation of autoimmune [85] or allergic diseases [86], which are often associated with infections, could in some cases be the result of initiating mechanisms. In autoimmunity, we hypothesize that T cells specific for autoantigens might not be recruited into tissues expressing the specific Ag peptides on APCs without the help

Evolution of antibody isotypes mediating initiation

CS- and DTH initiation can be induced by several antibody isotypes. In addition to the production of IgM by B-1 cells, B-2 cells account for some initiation by day 4 [7]. It is highly likely that B-2 cells first produce IgM, then later produce IgG₂ isotypes activating complement, and still later produce mast cell-sensitizing IgG₁ and IgE antibodies, which we have shown can initiate CS [30] (Figure 3). Thus, recruitment of allergen-specific Th2 cells into airways in established clinical allergic

Conclusions

Elicitation of CS and DTH begins with an initiation process that results in T-cell recruitment. In fact, there are two starting points, both involving cells of the innate immune system. The first of these is induction of the initiation process. The other is actual initiation of the late elicited effector phase due to recruitment of the T cells. Induction of the initiating process, which subsequently elicits T-cell recruitment, begins within minutes of immunization by postulated release of

Acknowledgements

We are indebted to Marilyn Avallone for her secretarial skills, and to Maria Leite de Moraes, Richard Kalish, Neel Dey, Weily Soong, and especially Carl Waltenbaugh for critical review of the manuscript. This work was supported in part by grants from the NIH [AI-059801 and AI-07174] and the American Academy of Allergy, Asthma, and Immunology to PWA, and by a grant from the Polish Committee of Scientific Research to MS.

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The contact hypersensitivity response (CHS) is a mouse model of allergic contact dermatitis in humans. The reaction is classified as type IV hypersensitivity and underlies many autoimmune disorders. Experiments employing the CHS model in wild-type mice showed that the protein antigen applied to the skin in the form of a gauze patch one week before the induction of Th1-dependent CHS was an effective strategy to reduce the inflammatory response in the skin. The approach of epicutaneous (EC) immunization also effectively suppressed the inflammatory response in various mouse models of autoimmune diseases.
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Our data show that EC immunization with TNP-conjugated protein antigen followed by induction of CHS to trinitrochlorobenzene (TNCB), effectively suppressed the CHS response as described by ear swelling, MPO activity in ear extracts, and the number of TCRβ⁺CD4⁺IFN-γ⁺ CHS T-effector cells in auxiliary and inguinal lymph nodes (ALN) and spleen (SPL) of HLA-DR4 tg mice. EC-induced suppression increases the frequency of CD11c⁺IL-10⁺ DCs in SPL. Their immunoregulatory role was confirmed by s.c. immunization with TNP-CD11c⁺DCs prior to CHS elicitation and induction.
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Germinated black soybean fermented with Lactobacillus pentosus SC65 alleviates DNFB-induced delayed-type hypersensitivity in C57BL/6N mice
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Rhynchosia nulubilis (black soybean) has many applications in oriental medicine. It is traditionally used to treat disease related with high blood pressure, diabetes, inflammation, and osteoporosis. Furthermore, fermented soybean foods have traditionally been used for immunity enhancement in East Asia. However, the anti-inflammatory effects of germinated R. nulubilis (GR) against delayed-type hypersensitivity (DTH) are not fully understood.
This study aimed to investigate the anti-inflammatory effects of germinated Rhynchosia nulubilis (GR) fermented with the lactic acid bacterium Lactobacillus pentosus SC65 (GR-SC65) isolated from pickled burdock.
We investigated the effects of GR-SC65 (300 mg/kg/day) on ear thickness and immune cell infiltration in DNFB-induced DTH in mice. We used dexamethasone (3 mg/kg) as a reference drug. Changes in infiltration of CD4⁺ and CD8⁺ T cells and NK cells were examined by immunohistochemistry. In addition, we investigated cytokine and chemokine production related to DTH using reverse transcription-polymerase chain reaction. We also investigated DTH-related cytokine production using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells.
Two lactic acid bacterial strains (Lactobacillus pentosus SC65 and Pediococcus pentosaceus ON81A) were selected for fermenting GR due to their high 2,2–diphenyl–1–picrylhydrazyl (DPPH) radical-scavenging activity. The total polyphenol contents (TPCs) in GR-SC65 and GR-ON81A were higher than that in unfermented GR (∗∗∗P < 0.001 vs. GR). Content of daidzein, glycitein, and genistein, the deglycosylated form of isoflavonoids, was higher in GR-SC65 than in unfermented GR. The ethanol extracts of GR-SC65 exerted a stronger anti-inflammatory activity than GR by inhibiting pro-inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in LPS-induced RAW264.7 macrophages. GR-SC65 reduced 1-fluoro-2,4-dinitrofluorobenzene (DNFB)-induced ear swelling and hyperplasia as well as vascular permeability. Fewer infiltrated CD4⁺ and CD8⁺ T cells were observed in the ear tissue of the GR-SC65-treated mice than those of the unfermented GR-treated mice. Furthermore, fewer infiltrated NK cells were observed in the GR-SC65 treated mice, than in the GR-treated mice. GR-SC65 significantly diminished the levels of CCL5 and COX-2 mRNAs and increased the level of IL-10 mRNA.
These data suggest that GR-SC65 can be used as a health supplement or a prophylactic against delayed-type hypersensitive inflammatory disease.
Transdermal immunotherapy: Past, present and future
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The studies of dermal application induced suppression were inspired by earlier observations showing that epicutaneous (EC) application of protein antigen on the skin in a form of a gauze dressing (patch method) induces the synthesis of IL-4 and IL-13, which may potentially inhibit the immune response mediated by CD4+ Th1 lymphocytes [38,39]. In the studies the model of Th1-dependent contact sensitivity reaction (CS) in mice was used (Fig. 1) [40]. In order to verify whether the EC application of protein antigen may inhibit the progress of inflammatory reaction with the participation of Th1 cells, 2,4,6-trinitrophenyl-conjugated mouse immunoglobulins (TNP-Ig) were administered on days 0 and 4 in a form of a gauze dressing with an attached patch, onto the shaved skin on the back of the mice.
The human skin plays an important role in thermal regulation, the maintenance of the correct water and electrolyte balance; it is also the main source of the vitamin D for the organism. Moreover, the skin forms an effective barrier against microorganisms, protecting the organism against xenobiotics and harmful external factors. It must also be mentioned that the skin is an essential organ involved in immunological mechanisms. This article summarizes current knowledge about skin-induced suppression induced via epicutaneous (EC) application of an antigen and is described in both Th1- and Tc1-mediated contact sensitivity (CS) in mice. The skin-induced suppression is also considered in the regulation of experimental models of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA) and colitis ulcerosa. Furthermore, the efficacy of treatment of multiple sclerosis (MS) patients with EC immunization is discussed. Second part of this review introduces new subject of immunopotentiation induced via EC immunization with an antigen in the presence of various pathogen-associated molecular patterns (PAMPs). Finally, the review describes dermal immunization in the therapy of allergic diseases.
Epicutaneous immunization with ovalbumin and CpG induces T<inf>H</inf>1/T<inf>H</inf>17 cytokines, which regulate IgE and IgG<inf>2a</inf> production
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We sought to determine whether epicutaneous treatment with antigen in the presence of a Toll-like receptor 9 agonist can suppress T_H2-mediated responses in an antigen-specific manner.
Epicutaneous immunization was performed by applying a skin patch soaked with ovalbumin (OVA) plus CpG, and its suppressor activity was determined by using the mouse model of atopic dermatitis. Finally, adoptive cell transfers were implemented to characterize the regulatory cells that are induced by epicutaneous immunization.
Epicutaneous immunization with OVA and CpG reduces the production of OVA-specific IgE and increases the synthesis of OVA-specific IgG_2a antibodies in an antigen-specific manner. Moreover, eosinophil peroxidase activity in the skin and production of IL-4, IL-5, IL-10, and IL-13 are suppressed. The observed reduction of IgE synthesis is transferable with T-cell receptor (TCR) αβ⁺CD4⁺CD25⁻ cells, whereas IgG_2a production is dependent on both TCRαβ⁺ and TCRγδ⁺ T cells. Further experiments show that the described phenomenon is myeloid differentiation primary response 88, IFN-γ, and IL-17A dependent. Finally, the results suggest that epicutaneous immunization with OVA and CpG decreases the synthesis of OVA-specific IgE and skin eosinophil peroxidase activity in mice with ongoing skin allergy.
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Inhibitory effect of antidepressant drugs on contact hypersensitivity reaction is connected with their suppressive effect on NKT and CD8+ T cells but not on TCR delta T cells
2015, International Immunopharmacology
Citation Excerpt :
The B-1 B lymphocytes were activated within 1 h post immunization and produced IgM antibodies. Upon local skin challenge with hapten, IgM antibodies form immune complexes with the antigen, which activate complement cascade, to generate C5a that stimulates mast cells to secrete tumor necrosis factor (TNF)-α and serotonin involved in T cell recruitment [4]. Campos et al. [5] also reported that innate-like invariant Vα14+ Jα18+ NKT (iNKT) cells were required to activate the B-1 B lymphocytes along with the antigen by producing IL-4 within minutes after immunization.
Contact hypersensitivity (CHS) reaction induced by a topical application of hapten is a cell-mediated antigen-specific type of skin inflammation mediated by interaction of several subtypes of T cell subpopulations. Recently, it has been shown that antidepressant drugs inhibit CHS reaction, although the mechanism of this effect remains unknown. The aim of the present study was to investigate the effect of 2-week desipramine or fluoxetine administration on the CHS reaction induced by picryl chloride (PCL) application in B10.PL mice and in knock-out mice established on B10.PL background: TCRδ^−/− mice lacking TCRγδ T lymphocytes; β₂m^−/− mice lacking CD8⁺ T lymphocytes and CD1d^−/− mice lacking CD1d dependent natural killer T (NKT) lymphocytes.
B10.PL, TCRδ^−/−, β₂m^−/− and CD1d^−/− mice were divided into six groups: 1) vehicle-treated negative control group; 2) desipramine-treated negative control group; 3) fluoxetine-treated negative control group; 4) vehicle and PCL-treated group (positive control group); 5) desipramine and PCL-treated group; and 6) fluoxetine and PCL-treated group. CHS to PCL was tested by evaluation of ear swelling. Metabolic activity of spleen and lymph node cells were estimated by MTT test.
The antidepressants significantly suppressed the CHS reaction in B10.PL mice: desipramine by 55% and fluoxetine by 42% compared to the positive control. This effect was even stronger in TCRδ^−/− mice, in which fluoxetine reduced the ear swelling by 73% in comparison with the vehicle-treated positive control group. On the other hand, desipramine and fluoxetine did not inhibit CHS reaction in β₂m^−/− and CD1d^−/− mice. Moreover, PCL increased metabolic and/or proliferative activity of splenocytes in all four strains of mice whereas the antidepressants decreased this activity of splenocytes in B10.PL, TCRδ^−/− and CD1d^−/− mice.
The results of the present study show that lack of CD8⁺ T cells or NKT cells abolishes the immunosuppressive effect of antidepressant drugs on PCL-induced CHS reaction in mice. These results suggest that antidepressant drug-induced inhibition of CHS reaction is connected with their inhibitory effect on ability of CD8⁺ T cells and NKT cells to induce and/or escalate CHS reaction. TCRγδ cells seem not to be involved in antidepressant-induced suppression of CHS.
Skin-induced tolerance as a new needle free therapeutic strategy
2014, Pharmacological Reports
Citation Excerpt :
Moreover, it is believed that a special mucosal milieu may create tolerogenic dendritic cells that induce different populations of regulatory cells. Although the skin is considered an organ where immune responses are easily induced [3], little attention has been given to skin induced tolerance [37]. Because skin and mucosa play similar function in our bodies (i.e. as a barrier to external pathogens) it is possible that epicutaneous (EC) application of antigen, apart from inducing a strong immune response, may also induce suppression in the periphery.
This article summarizes current knowledge about a new subject called “skin induced tolerance”. Suppression is induced via epicutaneous (EC) immunization with a protein antigen and is described in Th1, Tc1 and NK mediated contact hypersensitivity (CHS) reactions. The subject of skin-induced suppression is also described in the regulation of experimental models of autoimmune diseases like experimental autoimmune encephalomyelitis (EAE), collagen induced arthritis (CIA) and inflammatory bowel disease (IBD) and finally in an animal model of graft rejection. The potential clinical use of this approach to regulate human diseases is also discussed.

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Trends in Immunology

Extravascular T-cell recruitment requires initiation begun by Vα14+ NKT cells and B-1 B cells

Abstract

Section snippets

New view of the elicitation of CS and DTH

Elicitation of CS and DTH responses

The core of the initiation process

Induction of the initiating process

Detection of T-cell recruitment

Alternative initiating components and other initiating pathways

Possible initiation of T-cell recruitment in other systems

CD8 Tc1 responses and initiation

Clinical implications of differing Ag specificities of initiation versus effector phases

Evolution of antibody isotypes mediating initiation

Conclusions

Acknowledgements

Semin. Immunol.

J. Invest. Dermatol.

Cell. Immunol.

Cell. Immunol.

Trends Immunol.

Cell. Immunol.

Trends Immunol.

Immunity

J. Allergy Clin. Immunol.

IL-1α, but not IL-1β, is required for contact-allergen-specific T cell activation during the sensitization phase in contact hypersensitivity

Int. Immunol.

Contact hypersensitivity: the mechanism of immune responses and T cell balance

J. Interferon Cytokine Res.

An early component of delayed-type hypersensitivity mediated by T cells and mast cells

J. Exp. Med.

Adoptive transfer of early and late delayed-type hypersensitivity reactions mediated by human T cells

Reg. Immunol.

Required early complement activation in contact sensitivity with generation of C5-dependent chemotactic activity and late T cell IFN-γ: a possible initiating role of B cells

J. Exp. Med.

Early local generation of C5a initiates the elicitation of contact sensitivity by leading to early T cell recruitment

J. Immunol.

B cell-dependent T cell responses: IgM antibodies are required to elicit contact sensitivity

J. Exp. Med.

B-1 B cells mediate required early T cell recruitment to elicit protein induced delayed-type hypersensitivity

J. Immunol.

Possible involvement of C5/C5a in the efferent phase of contact sensitivity

J. Immunol.

T cell dependent mast cell degranulation and release of serotonin in murine delayed-type hypersensitivity

J. Exp. Med.

Defective elicitation of delayed-type hypersensitivity in W/Wv and S1/S1d mast cell deficient mice

J. Immunol.

Different mechanisms of release of vasoactive amines by mast cells occur in T cell-dependent compared to IgE-dependent cutaneous hypersensitivity responses

Eur. J. Immunol.

Mast cells control neutrophil recruitment during T cell-mediated delayed-type hypersensitivity reactions through tumor necrosis factor and macrophage inflammatory protein 2

J. Exp. Med.

Delayed-type hypersensitivity in mast cell deficient mice: dependence on platelets for expression of contact sensitivity

J. Immunol.

Tumor necrosis factor is a critical mediator in hapten-induced irritant and contact hypersensitivity reactions

J. Exp. Med.

Vascular endothelial cell expression of ICAM-1 and VCAm-1 at the onset of eliciting contact hypersensitivity in mice: evidence for a dominant role of TNF-α

J. Immunol.

Expression and function of C5a receptor in mouse microvascular endothelial cells

J. Immunol.

Human T cells express the C5a receptor and are chemoattracted to C5a

J. Immunol.

A new interpretation of the involvement of serotonin in delayed-type hypersensitivity: serotonin-2 receptor antagonists inhibit contact sensitivity by an effect on T cells

J. Immunol.

BLT for speed

Nat. Immunol.

Cutaneous immunization rapidly activates liver Vα14+invariant NKT cells to stimulate B-1 cells to initiate T cell recruitment to elicit contact sensitivity

J. Exp. Med.

Invariant Vα14 NKT lymphocytes: a double-edged immuno-regulatory T cell population

Eur. Cytokine Netw.

The regulatory role of Vα14 NKT cells in innate and acquired immune response

Annu. Rev. Immunol.

Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function

J. Exp. Med.

The responses of natural killer T cells to glycolipid antigens is characterized by surface receptor down-modulation and expansion

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

Initiation of delayed-type hypersensitivity by low doses of monoclonal IgE antibody. Mediation by serotonin and inhibition by histamine

J. Immunol.

Delayed-type hypersensitivity initiation by early-acting cells that are antigen mismatched or MHC incompatible with late-acting, delayed-type hypersensitivity effector T cells

J. Immunol.

Invest. Dermatol.

Extravascular T-cell recruitment requires initiation begun by Vα14⁺ NKT cells and B-1 B cells

Defective elicitation of delayed-type hypersensitivity in W/W^v and S1/S1^d mast cell deficient mice