ABSTRACT
Contact hypersensitivity (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 components 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 cell compartment regulates the development of effector CD8+ T cells during sensitization for CHS and discuss potential mechanisms that CD4+ T cells might utilize to mediate this regulation.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Dermatitis, Contact/immunology , Animals , Humans , Mice , Models, ImmunologicalABSTRACT
During sensitization with dinitrofluorobenzene for contact hypersensitivity (CHS) responses, hapten-specific CD8(+) T cells develop into IFN-gamma-producing cells, and CD4(+) T cells develop into IL-4/IL-5-producing cells. Administration of IL-12 during sensitization skews CD4(+) T cell development to IFN-gamma-producing cells, resulting in exaggerated CHS responses. In the current report we tested the role of IL-12 on CD8(+) T cell development during sensitization and elicitation of CHS to dinitrofluorobenzene. Administration of IL-12 during hapten sensitization induced the expression of IL-12Rbeta2 on both CD4(+) and CD8(+) T cells, augmented IFN-gamma production by these T cell populations, and increased the magnitude and duration of the CHS response to hapten challenge. CHS responses were virtually identical in wild-type and IL-12 p40(-/-) mice. Since engagement of CD40 on APC may stimulate IL-12 production, we also tested the role of CD40-CD154 interactions on the development of IFN-gamma-producing CD4(+) and CD8(+) T cells following hapten sensitization. Development of IFN-gamma-producing CD4(+) T cells during hapten sensitization was absent in wild-type mice treated with anti-CD154 mAb or in CD154(-/-) mice. In contrast, the absence of CD40-CD154 signaling had little or no impact on the development of IFN-gamma-producing CD8(+) T cells. These results demonstrate that the development of hapten-specific Th1 effector CD4(+) T cells in CHS requires both CD40-CD154 interactions and IL-12, whereas the development of IFN-gamma-producing effector CD8(+) T cells can occur independently of these pathways.
Subject(s)
Adjuvants, Immunologic/physiology , Antibodies, Monoclonal/pharmacology , CD40 Ligand/immunology , CD8-Positive T-Lymphocytes/immunology , Dermatitis, Contact/immunology , Growth Inhibitors/pharmacology , Immunosuppressive Agents/pharmacology , Interleukin-12/physiology , Adjuvants, Immunologic/administration & dosage , Administration, Cutaneous , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/pathology , Cell Differentiation/immunology , Dermatitis, Contact/pathology , Female , Growth Inhibitors/antagonists & inhibitors , Immunosuppressive Agents/antagonists & inhibitors , Interferon-gamma/biosynthesis , Interleukin-12/administration & dosage , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Receptors, Interleukin/biosynthesis , Receptors, Interleukin-12 , Recombinant Proteins/administration & dosage , Up-Regulation/immunologyABSTRACT
The primary effector cells of contact hypersensitivity (CHS) responses to dintrofluorobenzene (DNFB) are IFN-gamma-producing CD8(+) T cells, whereas CD4(+) T cells regulate the magnitude and duration of the response. The requirement for CD40-CD154 engagement during CD8(+) and CD4(+) T cell priming by hapten-presenting Langerhans cells (hpLC) is undefined and was tested in the current study. Similar CHS responses to DNFB were elicited in wild-type and CD154(-/-) animals. DNFB sensitization of CD154(-/-) mice primed IFN-gamma-producing CD8(+) T cells and IL-4-producing CD4(+) T cells. However, anti-CD154 mAb MR1 given during hapten sensitization inhibited hapten-specific CD8(+), but not CD4(+), T cell development and the CHS response to challenge. F(ab')(2) of MR1 failed to inhibit CD8(+) T cell development and the CHS response suggesting that the mechanism of inhibition is distinct from that of CD40-CD154 blockade. Furthermore, anti-CD154 mAb did not inhibit CD8(+) T cell development and CHS responses in mice depleted of CD4(+) T cells or in CD4(-/-) mice. During in vitro proliferation assays, hpLC from mice treated with anti-CD154 mAb during DNFB sensitization were less stimulatory for hapten-primed T cells than hpLC from either control mice or mice depleted of CD4(+) T cells before anti-CD154 mAb administration. These results demonstrate that development of IFN-gamma-producing CD8(+) T cells and the CHS response are not dependent on CD40-CD154 interactions. This study proposes a novel mechanism of anti-CD154 mAb-mediated inhibition of CD8(+) T cell development where anti-CD154 mAb acts indirectly through CD4(+) T cells to impair the ability of hpLC to prime CD8(+) T cells.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD40 Antigens/metabolism , CD40 Ligand/metabolism , CD8-Positive T-Lymphocytes/immunology , Dermatitis, Contact/immunology , Administration, Cutaneous , Animals , Antibodies, Monoclonal/administration & dosage , Antigen Presentation/immunology , CD4-Positive T-Lymphocytes/metabolism , CD40 Ligand/biosynthesis , CD40 Ligand/genetics , CD40 Ligand/immunology , CD8-Positive T-Lymphocytes/metabolism , Cell Communication/immunology , Cell Differentiation/immunology , Dermatitis, Contact/prevention & control , Dinitrofluorobenzene/administration & dosage , Dinitrofluorobenzene/immunology , Female , Growth Inhibitors/administration & dosage , Haptens/administration & dosage , Haptens/immunology , Haptens/metabolism , Immunization , Injections, Intraperitoneal , Interferon-gamma/biosynthesis , Langerhans Cells/immunology , Langerhans Cells/metabolism , Lymphocyte Activation , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
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.
Subject(s)
Dermatitis, Contact/immunology , Lymphocyte Activation/immunology , T-Lymphocytes/immunology , Animals , Antigen Presentation/immunology , B7-1 Antigen/immunology , CD28 Antigens/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Cytokines/immunology , Haptens/immunology , Humans , Signal Transduction/immunologyABSTRACT
Recent studies have suggested a pivotal role for secondary lymphoid chemokine (SLC) in directing dendritic cell trafficking from peripheral to lymphoid tissues. As an extension of these studies, we examined the consequences of anti-SLC Ab treatment during Ag priming on T cell function in an inflammatory response. We used a model of T cell-mediated inflammation, contact hypersensitivity (CHS), where priming of the effector T cells is dependent upon epidermal dendritic cell, Langerhans cells, and migration from the hapten sensitization site in the skin to draining lymph nodes. A single injection of anti-SLC Ab given at the time of sensitization with FITC inhibited Langerhans cell migration into draining lymph nodes for at least 3 days. The CHS response to hapten challenge was inhibited by anti-SLC Ab treatment in a dose-dependent manner. Despite the inhibition of CHS, T cells producing IFN-gamma following in vitro stimulation with anti-CD3 mAb or with hapten-labeled cells were present in the skin-draining lymph nodes of mice treated with anti-SLC Ab during hapten sensitization. These T cells were unable, however, to passively transfer CHS to naive recipients. Animals treated with anti-SLC Ab during hapten sensitization were not tolerant to subsequent sensitization and challenge with the hapten. In addition, anti-SLC Ab did not inhibit CHS responses when given at the time of hapten challenge. These results indicate an important role for SLC during sensitization for CHS and suggest a strategy to circumvent functional T cell priming for inflammatory responses through administration of an Ab inhibiting dendritic cell trafficking.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Chemokines, CC/immunology , Dermatitis, Contact/immunology , Haptens/immunology , Lymphocyte Activation/immunology , T-Lymphocytes/immunology , Adoptive Transfer , Animals , Cell Migration Inhibition , Chemokine CCL21 , Cytokines/biosynthesis , Dermatitis, Contact/etiology , Dermatitis, Contact/prevention & control , Dinitrofluorobenzene/administration & dosage , Dinitrofluorobenzene/immunology , Female , Haptens/administration & dosage , Immune Tolerance/immunology , Immunization , Injections, Intravenous , Langerhans Cells/cytology , Langerhans Cells/immunology , Mice , Mice, Inbred BALB C , Oxazolone/administration & dosage , Oxazolone/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/transplantationABSTRACT
The tissue-specific antigen associated with human lung adenocarcinoma had been investigated using immunological and biochemical methods. The antigen, which represents a new tissue-specific marker, has a molecular weight of 400 kDa. Purification of the antigen was achieved by gel chromatography. Antibody binding to the antigen was studied using enzyme-linked immunoassay after preincubation with enzymes or treatment with periodate. The results obtained testify to the proteinaceous nature of the antigenic determinant and the glycoprotein nature of the antigen.