The role of dendritic cells in contact hypersensitivity

Abstract

Contact hypersensitivity (CHS) is a hapten-specific skin inflammation mediated by T cells that recognize haptenated peptides presented by major histocompatibility complex (MHC) class I and class II molecules on antigen-presenting cells (APCs). CHS is a self-limited inflammation of short duration which peaks at 24 hours after challenge. CHS spontaneously resolves in a few days, suggesting the existence of potent downregulatory mechanisms which control and/or block the effector cells of contact sensitivity (CS).In a recent Review article on the pathophysiology of CHS, Stephan Grabbe and Thomas Schwarz stressed the differences between CHS and classical delayed-type hypersensitivity (DTH) reactions to proteins [1xGrabbe, S. and Schwarz, T. Immunol. Today. 1998; 19: 37–44Abstract | Full Text PDF | PubMed | Scopus (413)See all References[1]. Whereas DTH responses are mediated by CD4+ effector cells, it has been reported that the CHS inflammatory reaction is mediated by CD8+ effector cells and that CD4+ T cells are endowed with downregulatory properties [2xBour, H., Peyron, E., Gaucherand, M. et al. Eur. J. Immunol. 1995; 25: 3006–3010Crossref | PubMedSee all References, 3xXu, H., Diiulio, N.A., and Fairchild, R.L. J. Exp. Med. 1996; 183: 1001–1012Crossref | PubMedSee all References]. These observations raised the question of the nature of the APCs responsible for priming the hapten-specific CD4+ and CD8+ T cells. Although epidermal dendritic cells (DCs) (Langerhans cells; LCs) have been shown to induce effector cells of CHS, it was hypothesized that they were not responsible for the priming of downregulatory CD4+ cells, instead a special type of APC, lacking appropriate costimulatory signals, could be involved in the phenomenon [1xGrabbe, S. and Schwarz, T. Immunol. Today. 1998; 19: 37–44Abstract | Full Text PDF | PubMed | Scopus (413)See all References[1].We recently addressed the question of the nature of the APC responsible for the priming of downregulatory T cells, in the murine model of CHS induced by treatment with the contact allergen 2,4-dinitrofluorobenzene (DNFB) in which CD8+ cells are effector cells of CS and CD4+ cells behave as downregulatory cells [2xBour, H., Peyron, E., Gaucherand, M. et al. Eur. J. Immunol. 1995; 25: 3006–3010Crossref | PubMedSee all References[2]. Mature DCs were either generated from the skin after overnight culture in granulocyte–macrophage colony-stimulating factor (GM-CSF) or generated in vitro from bone marrow progenitors of wild-type C57BL/6 as well as of β2-microglobulin-deficient (β2-m−/−) and Aβ−/− mice, which are genetically deficient in MHC class I or MHC class II molecules, respectively. These DCs, expressing a mature DC phenotype (CD11c+, DEC-205+, B7-1+, B7-2+, CD40+ and MHC class IIhi), were haptenated in vitro and injected into naive C57BL/6 wild-type recipients which five days later received a cutaneous application of DNFB on the ears. These experiments demonstrated that MHC class I molecules on DCs were mandatory for the induction of CHS reaction inasmuch as DCs recovered from wild-type C57BL/6 [class I+/class II+ (I+/II+)] and Aβ−/− (I+/II−) mice, but not from β2-m−/− (I−/II+), could prime for CHS (Ref. [4xKrasteva, M., Kehren, J., Horand, F. et al. J. Immunol. 1998; 160: 1181–1190PubMedSee all References[4]). Although II+/I− DCs could not sensitize for CS they could prime for hapten-specific CD4+ T cells in the lymphoid organs. More importantly, haptenated II+/I− DCs could induce a down-regulation of CS reaction when injected in wild-type C57BL/6 recipient mice at the time of cutaneous sensitization. Thus, the same type of APC, i.e. mature DCs, which have the remarkable property of presenting exogenous antigens on both MHC class I and MHC class II molecules [5xShen, Z.H., Reznikoff, G., Dranoff, G., and Rock, K.L. J. Immunol. 1997; 158: 2723–2730PubMedSee all References[5], can simultaneously and independently prime for MHC class I-restricted effectors and MHC class II-restricted downregulatory T cells [4xKrasteva, M., Kehren, J., Horand, F. et al. J. Immunol. 1998; 160: 1181–1190PubMedSee all References[4]. It is most likely that skin LCs are involved in processing of haptens bound on self or exogenous proteins into peptides associated to MHC class I and MHC class II molecules [6xLepoittevin, J.P. and Leblond, I. Eur. J. Dermatol. 1997; 7: 151–154See all References[6]and that upon migration to the draining lymph nodes they become efficient in activation of both CD4+ and CD8+ T hapten-specific precursors. Finally, these data suggest that targeting haptens on MHC class II molecules on epidermal DCs could be used to induce antigen-specific tolerance in CHS.