- Email: [email protected]
Dendritic cells in contact sensitivity
LYMPHOID
DENDRITIC
CELLS
907
DENDRITIC CELLS IN CONTACT SENSITIVITY
S.C. Knight Clinical Research Centre, Watford Rd., Harrow, Middlesex (UK)
Pathway of contact sensitization. Studies of contact sensitivity were the first to provide indicators that Langerhans cells (LC) are the antigenpre~enting cells of the skin. Silberberg (1971) observed lymphocytes in close contact with LC in skin in contact allergic reactions in humans. In the same year, Birbeck granules characteristic of LC (Birbeck et al., 1961) were recognized as endocytic organelles (Hashimoto, 1971); the relevance of this to antigen processing and presentation has been indicated more recently by the identification of HLA class II molecules as constituents of these granules (Hanau et ai., 1987). Following epicutaneous exposure to contact sensitizers, some LC may move from the dermis to the epidermi~ tn h~ l,~t hy desq,,~m~t;on (Kaplan et al., 1987). However, many LC within the dermis or returning to it enter the dermal lymphatics as migratory veiled cells leading to a transient depletion of LC from the skin (Hunziker-Winkelmann, 1978; Hanau et aL, 1989). Veiled cells then enter the lymph nodes and become the interdigitating cells (IDC) of the paracortex (Silberberg-Sinakin, 1980; Hoefsmit et al., 1982; Knight, 1990). The final evidence for this pathway for contact sensitization comes from studies of the IDC isolated as DC; IDC and DC share the same marker in mice (Kraal et al., 1986) and both may carry Birbeck granules when taken from mice recently skin-sensitized with fluorescein isothiocyanate (FITC) (Macatonia et al., 1987). DC isolated from lymph nodes of mice recently exposed to FITC (8 hours-3 days previously) initiate pro-
liferative and cytotoxic responses specific for the antigen in T cells from syngeneic naive animals. They also induced delayed hypersensitivity, and specific antibody production in recipient mice which develops several days after cell transfer. Trolls which transfer immediate contact sensitivity appear 3-6 days after skin sensitization (Macatonia et al., 1989a). After this sensitization phase, or on a second exposure to antigen, LC may become targets of the immune responses (Silberberg-Sinakin et al., 1977). Studies of presentation of influenza virus by mouse DC to produce primary cytotoxic responses in vitro (Macatonia et al., 1989b) have been extended to show that DC can be targets for T lymphocytes (Taylor, Macatonia, Askonas and Knight, in preparation). If phocytes, this provides a feedback system for switching off stimulation of T cells which could be operating in contact sensitivity.
Activation of DC. Maturational steps have been established via which LC, with some macrophage-like features, mature to cells which are phenotypically and functionally DC (Witmer-Pack et al., 1987). Similar changes are also induced by epicutaneous exposure to contact sensitizer. Membrane ATPase activity is lost and the numbers of coated pits and vesicles, endosomes and lysosomes increase, which is suggestive of receptormediated endocytosis (Hanau et al., 1989). Within the lymph node 24 h after exposure to FITC, some DC carry high
908
28 th F O R U M I N I M M U N O L O G Y
levels of antigen and cause activation of syngeneic T cells (Macatonia et al., 1989). These cells also have a more "activated" appearance, with prominent Golgi and many more lysosomes than are seen in those DC which carry little or no antigen and do not stimulate immune responses. In other systems, endocytosed antigen has been shown to influence the synthesis and structure of the MHC class I/antigen complex appearing on the cell surface, which can then act as a target for cytotoxic T cells (Townsend et al., 1989). It may be that a similar induction of stimulatory class II antigen structures at the surface of LC of DC is occurring during this "activation" process following skinpainting with contact sensitizer. However, additional features in the handling of contact sensitizers are emerging. Some DC expressing antigen appear in lymph nodes within minutes of exposure to FITC (Macatonia et al., 1987) but do not stimulate T cells. This is consistent with the idea that antigen directly haptenated to the surface of DC is not stimulatoD until some "processing" or antigen-handling has occurred. DC directly haptenated with antigen in vitro were not stimulatory for T cells stringently depleted of DC unless small numbers of DC which had not been exposed to antigen were added (Macatonia and Knight, in preparation). Replacement of either DC population with other Ia-bearing cells did not result in stimulation. The DC with antigen thus acted synergisqcally with DC not exposed directly to antigen, a conclusion consistent with the concept of interaction between directly haptenated and non-haptenated accessory cells suggested by Thomas et al. (1977). Thus, processing events and D C / D C interactions might contribute to the potency of DC in initiating contact sensitivity.
(Schuler and Steinman, 1985) and the antigen itself may promote DC development. However, additional factors influence the movement and functions of DC. Accumulation of DC with antigen in lymph nodes on contact sensitization is not dependent on mature T cells, since it occurs in neonatally thymectomized pigs and in nude mice (Drexhage et al., 1979; Knight et al., 1985a,b). More surprisingly, antigen carried by DC does not appear to be the signal causing movement. Two points suggest this view. First, in skin-painted mice treated with cyclosporin A which fail to develop contact sensitivity, DC enter the draining lymph nodes but bear little detectable antigen (Knight et al., 1988). In addition, after local skin painting with FITC, DC numbers increase not only in draining nodes but also in contralateral and distal nodes (Hill, Edwards, Kimber and Knight, in preparation). These cells do not carry detectable antigen and do not stimulate significant T-cell proliferation in vitro. The systemic signal for DC movement and the functional significance of this effect are not known. The numbers of DC present in the skin may also influence the level of contact sensitization (Gilchrist et al., 1982; Toews et al., 1980; Belsito et al., 1987). The blocking effects of ultraviolet irradiation or glucocorticos~eroids on development of responses also appear to act via LC in the skin (Green et al., 1979; Aberer et al., 1981). Another dendriform cell (the Thy-I + cell) in the skin has also been postulated as an immunoregulatory influence, and it has even been suggested that this cell may present antigen to suppressor cells (Bergstresser et al., 1983 ; Romani et ai., 1985; Sullivan et al., 1986). The nature of the relationships between LC and T h y l * cells, and CD4+ and CD8* lyn~.phocytes in contact sensitization, remare to be clarified.
Modulation of contact sensitivity. Stages of development of DC presenting contact sensitizer to T cells can be demonstrated, but factors which influence this life history are not well understood. Cytokines such as GM-CSF
Summary. Bone-marrow-derived DC, passing through the skin or residing there as LC, acquire antigen following epicutaneous
LYMPHOID
DENDRITIC
exposure to contact sensitizer. They move as veiled cells in the afferent lymphatics and migrate to draining lymph nodes, where they become mterdigitating cells of the paracortex. Here they initiate T-cell responses; the cytotoxic T cells and antibody formation which develop may be able to target on DC as well as other antigen-bearing cells, so producing feed-back mechanisms to switch off immune responses. Additional features include a systemic effect which leads to movement of DC without antigen into lymph
CELLS
909
nodes. What are the signals leading to this m o v e m e n t and w h a t is its significance? There is evidence for synergy between directly haptenated DC and DC not directly acquiring antigen. How does this occur and how important is this effect in ensuring the potency of DC in presenting contact sensitizer to T cells ? What is the importance of antigen processing by LC ? Finally, dendriform cells which may be of T-cell origin are also present in the skin. What is their role in modulating the development of contact sensitivity?
References. ABERER, W., SCHULER,G., HONGSMANN,H. & WOLFF,K. (1981), Ultraviolet light depletes surface markers of Langerhans cells. J. invest. Dermatol., 77, 202-210. BELSITO,D.V., DERSARKISSIAN,R.M., THORBECKE,G.J. & BAER,R.L. (1987), Reversal by lymphokines of the age-related hyporesponsiveness to contact sensitization and reduced Ia expression on Langerhans cells. Arch. Dermatol. Res., 279, 76-80. BERGSTRESSER, P.R., TIGELAAR,R.E., DEER, J.H. & STREILEIN, J.W. (1983), Thy-1 antigenbearing dendritic cells populate murine epidermis. J. invest. Dermatol., 81,286-288. BIRBECK, M.S., BREATHNACH,A.S. & EVERALL,J.D. (1961), An electron microscope study of basal melanocytes and high-level clear cells (Langerhans cells) in vitiligo. J. invest. Dermatol., 64, 37-51. DREXHAGE,H.A., MULLINK,n . , DE GROOT, J., CLARKE, J. 8£ BALFOUR,B.M. (1979), A study of cells present in peripheral lymph of pigs with special reference to a type of cell resembling the Langerhans cell. Cell Tissue Res., 202, 407-430. ~IIICHRF:.qT_ R_A__ Mlii~pI4v~ ~!7' ~ gn'r~R N A IIQRg~ ~ffPc't nf rhrnnnlngic" aoino and ultraviolet irradiation on Langerhans cells in human epidermis. J. invest. Dermatol., 79, 85-88. GREENE, M.I., SY, M.S., KRIPKE, M. & BENACERRAF,B. (1979), Impairment of antigenpresenting cell function by ultraviolet radiation. Proc. nat. Acad. Sci. (Wash.), 76, 6591-6595. HANAU.. D., FABRE, M., SCHMITT,D.A., LEPOITTEVIN,J.-P., STAMPF,J.-L., GROSSHANS,E., BENEZRA, C. ~ CAZENAVE, J.P. (1989), ATphase and morphologic changes in Langerhans cells induced by epicutaneous application of a sensitizing doses o.~ DNFB. J. invest. Dermatol., 92, 689-694. HASmMOTO, K. (1971), Langerhans' cell granule. An endocytic organe!le. Arch. Derrnatol., 194, 148-160. HOEFSMIT, E.C.M., DUIJVESTIN,A.M. & KAMPERDIJK,E.W.A. (1982), Relation between Langerhans cells, veiled cells and interdigitating cells. Immunobiol., 161, 255-265. HUNZIKER,N. & WINKELMANN,R.K. (1978), Langerhans cell in contact dermatitis of the guinea pig. Arch. Dermatol., 114, 1309-1313. KAPLAN,G., NUSRAT,A., WITMER, M.D., NATH, I. & COHN, Z. (1987), Distribution and turnover of Langerhans cells during delayed immune responses in human skin. J. exp. Med., 165, 763-776. KNmHT, S.C., BEDFORD,P.A. & HUNT, R. (I985a), Role of dendritic cells in the initiation of immune responses to contact sensitizers. - - II. Studies in nude mice. Cell Immunol., 94, 435-439. KNIGHT, S.C., KREJCI, J., MALKOVSKY,M., COLIZZI,V., GAUTAM,A. & ASHERSON,G.L. (1985b). The role of dendritic cells in the initiation of immun responses to contact sensitizers. - - I. In vivo exposure to antigen. Cell Immunol., 94, 427-434. KNIGHT,S.C. (1990), Dendritic cells, in "Clinical aspects of immunology" (Lachmann, P.J., Peters, D.K., Rosen, F.S. & Walport, M.J.). Blackwell Scientific Publ., Oxford (in press).
910
28 th F O R U M I N I M M U N O L O G Y
KNIGHT, S.C., ROBERTS,M., MACATONIA,S. & EDWARDS,A.J. (1988), Blocking of acquisition and presentation of antigen by dendritic cells with cyclosporin. Transplantation, 46, 49s-52s. KRAEL, G., BREEL,M., JANSE,K. & BRUIN, G. (1986), Langerhans cells, veiled cells and interdigitating cells in the mouse recognized by a monoclonal antibody. J. exp. Med., 163, 981-997. MACATONIA,S.E., KNIGHT,S.C., EDWARDS,A.J., GRIFFITHS,S. • FRYER, P. (1987), Localization of antigen on lymph node dendritic cells after exposure to the contact sensitizer fluorescein isothyiocyanate. Functional and morphological studies. J. exp. Med., 166, 1654-1657. MACATONIA,S.E. & KNIGHT,S.C. (1989a), Primary stimulation by dendritic cells induces antiviral proliferative and cytotoxic T~cell responses in vitro. J. exp. Med., 169, 1255-1264. MACATONIA,S.E. & KNIGHT,S.C. (1989b), Dendritic cells and T cells transfer sensitization for delayed-type hypersensitivity after skin-painting with contact sensitizer. J. Immunol., 66, 96-99. ROMANI, N., STINGL,G., TSCHACHLER,E., WITMER,M.D., STEINMAN,R.M., SHEVACH,E.M. & SCHULER, G. (1985), The Thy-l-bcaring cell of murine epidermis: a distinctive leukocyte perhaps related to natural killer cells. J. exp. Med., 161, 1368-1383. SCHULER,G. ~ STEINMAN,R.M. (1985), Murine epidermal Langerhans cells mature into potent immunostimuiatory dendritic cells in vitro. J. exp. Med., 161, 526-546. SILBERBERG,I. (1971), Studies by electron microscopy of epidermis after topical application of mercuric chloride. Morphologic and histochemical findings in epidermal cells of human subjects who do not show allergic sensitivity or primary irritant reactions to mercuric chloride (0.1%). J. invest. Dermatol., 64, 37-51. SILBERBERG-SINAKIN,I., FEDORKO, M.E., BAER, R.L., ROSENTHAL,S.A., BERESOWSKY,V. ~g: THORBECKE,G. (1977), Langerhans cells target cells in immune complex reactions. Cell lmmunoL , 32, 400-416. SILBERBERG-SINAKIN,I., GIGLI,I., BAER,R.L. & THORBECKE,G.T. (1980), Langerhans cells" role in contact hypersensitivity and relationship to lymphoid dendritic cells and macrnrhages. Immunol. Rev., 53, 203-237. SULLIVAN,S., BERGSTRESSER,P.R., TIGELAAR,R.E. & STREILEIN,J.W. (1986), Induction and regulation of contact hypersensitMty by resident, bone-marrow-derived, dendritic epidezmal ceils: Laagerhans cells and Thy-! + epidermal cells. J. Immunol., 137, 2460-2467. THOMAS,D.W., FORNI,G., SHEVACH,E.M. & GREEN,I. (1977), The role of the macrophages as the stimulator cell in contact sensitivity. J. Immunol., 124, 1503-1506. ToEws, G.B., BERGSTRESSER.P.R. & StrEllr:tN, l W (IOr/~), l~pirl~rmal I . . . . . h . . . . . !! ,4~,-. sity determines whether contact sensitivity or unresponsiveness follows skin painting with DNFB. J. Immunol., 124, 445-453. TOWNSEND, A., OHLEN, C., BASTIN, J., LJUNGGREN,H.-G., FOSTER, L. & KARRE, K. (1989), Association of class I major histocompatibility heavy and light chains induced by viral peptides. Nat:~re (Lond.), 340, 443-448. WITMER-PACK, M.D., OLIVIFP~,W., VALINSKY,J., SCHULER, G. ~ STEINMAN, R.M. (1987), Granulocyte/macrophage colony stimulating factor is essential for the viability and function of cultured murine epidermal Langerhans cells. J. exp. Med., 166, 1484-1498.
DENDRITIC
CELLS
907
DENDRITIC CELLS IN CONTACT SENSITIVITY
S.C. Knight Clinical Research Centre, Watford Rd., Harrow, Middlesex (UK)
Pathway of contact sensitization. Studies of contact sensitivity were the first to provide indicators that Langerhans cells (LC) are the antigenpre~enting cells of the skin. Silberberg (1971) observed lymphocytes in close contact with LC in skin in contact allergic reactions in humans. In the same year, Birbeck granules characteristic of LC (Birbeck et al., 1961) were recognized as endocytic organelles (Hashimoto, 1971); the relevance of this to antigen processing and presentation has been indicated more recently by the identification of HLA class II molecules as constituents of these granules (Hanau et ai., 1987). Following epicutaneous exposure to contact sensitizers, some LC may move from the dermis to the epidermi~ tn h~ l,~t hy desq,,~m~t;on (Kaplan et al., 1987). However, many LC within the dermis or returning to it enter the dermal lymphatics as migratory veiled cells leading to a transient depletion of LC from the skin (Hunziker-Winkelmann, 1978; Hanau et aL, 1989). Veiled cells then enter the lymph nodes and become the interdigitating cells (IDC) of the paracortex (Silberberg-Sinakin, 1980; Hoefsmit et al., 1982; Knight, 1990). The final evidence for this pathway for contact sensitization comes from studies of the IDC isolated as DC; IDC and DC share the same marker in mice (Kraal et al., 1986) and both may carry Birbeck granules when taken from mice recently skin-sensitized with fluorescein isothiocyanate (FITC) (Macatonia et al., 1987). DC isolated from lymph nodes of mice recently exposed to FITC (8 hours-3 days previously) initiate pro-
liferative and cytotoxic responses specific for the antigen in T cells from syngeneic naive animals. They also induced delayed hypersensitivity, and specific antibody production in recipient mice which develops several days after cell transfer. Trolls which transfer immediate contact sensitivity appear 3-6 days after skin sensitization (Macatonia et al., 1989a). After this sensitization phase, or on a second exposure to antigen, LC may become targets of the immune responses (Silberberg-Sinakin et al., 1977). Studies of presentation of influenza virus by mouse DC to produce primary cytotoxic responses in vitro (Macatonia et al., 1989b) have been extended to show that DC can be targets for T lymphocytes (Taylor, Macatonia, Askonas and Knight, in preparation). If phocytes, this provides a feedback system for switching off stimulation of T cells which could be operating in contact sensitivity.
Activation of DC. Maturational steps have been established via which LC, with some macrophage-like features, mature to cells which are phenotypically and functionally DC (Witmer-Pack et al., 1987). Similar changes are also induced by epicutaneous exposure to contact sensitizer. Membrane ATPase activity is lost and the numbers of coated pits and vesicles, endosomes and lysosomes increase, which is suggestive of receptormediated endocytosis (Hanau et al., 1989). Within the lymph node 24 h after exposure to FITC, some DC carry high
908
28 th F O R U M I N I M M U N O L O G Y
levels of antigen and cause activation of syngeneic T cells (Macatonia et al., 1989). These cells also have a more "activated" appearance, with prominent Golgi and many more lysosomes than are seen in those DC which carry little or no antigen and do not stimulate immune responses. In other systems, endocytosed antigen has been shown to influence the synthesis and structure of the MHC class I/antigen complex appearing on the cell surface, which can then act as a target for cytotoxic T cells (Townsend et al., 1989). It may be that a similar induction of stimulatory class II antigen structures at the surface of LC of DC is occurring during this "activation" process following skinpainting with contact sensitizer. However, additional features in the handling of contact sensitizers are emerging. Some DC expressing antigen appear in lymph nodes within minutes of exposure to FITC (Macatonia et al., 1987) but do not stimulate T cells. This is consistent with the idea that antigen directly haptenated to the surface of DC is not stimulatoD until some "processing" or antigen-handling has occurred. DC directly haptenated with antigen in vitro were not stimulatory for T cells stringently depleted of DC unless small numbers of DC which had not been exposed to antigen were added (Macatonia and Knight, in preparation). Replacement of either DC population with other Ia-bearing cells did not result in stimulation. The DC with antigen thus acted synergisqcally with DC not exposed directly to antigen, a conclusion consistent with the concept of interaction between directly haptenated and non-haptenated accessory cells suggested by Thomas et al. (1977). Thus, processing events and D C / D C interactions might contribute to the potency of DC in initiating contact sensitivity.
(Schuler and Steinman, 1985) and the antigen itself may promote DC development. However, additional factors influence the movement and functions of DC. Accumulation of DC with antigen in lymph nodes on contact sensitization is not dependent on mature T cells, since it occurs in neonatally thymectomized pigs and in nude mice (Drexhage et al., 1979; Knight et al., 1985a,b). More surprisingly, antigen carried by DC does not appear to be the signal causing movement. Two points suggest this view. First, in skin-painted mice treated with cyclosporin A which fail to develop contact sensitivity, DC enter the draining lymph nodes but bear little detectable antigen (Knight et al., 1988). In addition, after local skin painting with FITC, DC numbers increase not only in draining nodes but also in contralateral and distal nodes (Hill, Edwards, Kimber and Knight, in preparation). These cells do not carry detectable antigen and do not stimulate significant T-cell proliferation in vitro. The systemic signal for DC movement and the functional significance of this effect are not known. The numbers of DC present in the skin may also influence the level of contact sensitization (Gilchrist et al., 1982; Toews et al., 1980; Belsito et al., 1987). The blocking effects of ultraviolet irradiation or glucocorticos~eroids on development of responses also appear to act via LC in the skin (Green et al., 1979; Aberer et al., 1981). Another dendriform cell (the Thy-I + cell) in the skin has also been postulated as an immunoregulatory influence, and it has even been suggested that this cell may present antigen to suppressor cells (Bergstresser et al., 1983 ; Romani et ai., 1985; Sullivan et al., 1986). The nature of the relationships between LC and T h y l * cells, and CD4+ and CD8* lyn~.phocytes in contact sensitization, remare to be clarified.
Modulation of contact sensitivity. Stages of development of DC presenting contact sensitizer to T cells can be demonstrated, but factors which influence this life history are not well understood. Cytokines such as GM-CSF
Summary. Bone-marrow-derived DC, passing through the skin or residing there as LC, acquire antigen following epicutaneous
LYMPHOID
DENDRITIC
exposure to contact sensitizer. They move as veiled cells in the afferent lymphatics and migrate to draining lymph nodes, where they become mterdigitating cells of the paracortex. Here they initiate T-cell responses; the cytotoxic T cells and antibody formation which develop may be able to target on DC as well as other antigen-bearing cells, so producing feed-back mechanisms to switch off immune responses. Additional features include a systemic effect which leads to movement of DC without antigen into lymph
CELLS
909
nodes. What are the signals leading to this m o v e m e n t and w h a t is its significance? There is evidence for synergy between directly haptenated DC and DC not directly acquiring antigen. How does this occur and how important is this effect in ensuring the potency of DC in presenting contact sensitizer to T cells ? What is the importance of antigen processing by LC ? Finally, dendriform cells which may be of T-cell origin are also present in the skin. What is their role in modulating the development of contact sensitivity?
References. ABERER, W., SCHULER,G., HONGSMANN,H. & WOLFF,K. (1981), Ultraviolet light depletes surface markers of Langerhans cells. J. invest. Dermatol., 77, 202-210. BELSITO,D.V., DERSARKISSIAN,R.M., THORBECKE,G.J. & BAER,R.L. (1987), Reversal by lymphokines of the age-related hyporesponsiveness to contact sensitization and reduced Ia expression on Langerhans cells. Arch. Dermatol. Res., 279, 76-80. BERGSTRESSER, P.R., TIGELAAR,R.E., DEER, J.H. & STREILEIN, J.W. (1983), Thy-1 antigenbearing dendritic cells populate murine epidermis. J. invest. Dermatol., 81,286-288. BIRBECK, M.S., BREATHNACH,A.S. & EVERALL,J.D. (1961), An electron microscope study of basal melanocytes and high-level clear cells (Langerhans cells) in vitiligo. J. invest. Dermatol., 64, 37-51. DREXHAGE,H.A., MULLINK,n . , DE GROOT, J., CLARKE, J. 8£ BALFOUR,B.M. (1979), A study of cells present in peripheral lymph of pigs with special reference to a type of cell resembling the Langerhans cell. Cell Tissue Res., 202, 407-430. ~IIICHRF:.qT_ R_A__ Mlii~pI4v~ ~!7' ~ gn'r~R N A IIQRg~ ~ffPc't nf rhrnnnlngic" aoino and ultraviolet irradiation on Langerhans cells in human epidermis. J. invest. Dermatol., 79, 85-88. GREENE, M.I., SY, M.S., KRIPKE, M. & BENACERRAF,B. (1979), Impairment of antigenpresenting cell function by ultraviolet radiation. Proc. nat. Acad. Sci. (Wash.), 76, 6591-6595. HANAU.. D., FABRE, M., SCHMITT,D.A., LEPOITTEVIN,J.-P., STAMPF,J.-L., GROSSHANS,E., BENEZRA, C. ~ CAZENAVE, J.P. (1989), ATphase and morphologic changes in Langerhans cells induced by epicutaneous application of a sensitizing doses o.~ DNFB. J. invest. Dermatol., 92, 689-694. HASmMOTO, K. (1971), Langerhans' cell granule. An endocytic organe!le. Arch. Derrnatol., 194, 148-160. HOEFSMIT, E.C.M., DUIJVESTIN,A.M. & KAMPERDIJK,E.W.A. (1982), Relation between Langerhans cells, veiled cells and interdigitating cells. Immunobiol., 161, 255-265. HUNZIKER,N. & WINKELMANN,R.K. (1978), Langerhans cell in contact dermatitis of the guinea pig. Arch. Dermatol., 114, 1309-1313. KAPLAN,G., NUSRAT,A., WITMER, M.D., NATH, I. & COHN, Z. (1987), Distribution and turnover of Langerhans cells during delayed immune responses in human skin. J. exp. Med., 165, 763-776. KNmHT, S.C., BEDFORD,P.A. & HUNT, R. (I985a), Role of dendritic cells in the initiation of immune responses to contact sensitizers. - - II. Studies in nude mice. Cell Immunol., 94, 435-439. KNIGHT, S.C., KREJCI, J., MALKOVSKY,M., COLIZZI,V., GAUTAM,A. & ASHERSON,G.L. (1985b). The role of dendritic cells in the initiation of immun responses to contact sensitizers. - - I. In vivo exposure to antigen. Cell Immunol., 94, 427-434. KNIGHT,S.C. (1990), Dendritic cells, in "Clinical aspects of immunology" (Lachmann, P.J., Peters, D.K., Rosen, F.S. & Walport, M.J.). Blackwell Scientific Publ., Oxford (in press).
910
28 th F O R U M I N I M M U N O L O G Y
KNIGHT, S.C., ROBERTS,M., MACATONIA,S. & EDWARDS,A.J. (1988), Blocking of acquisition and presentation of antigen by dendritic cells with cyclosporin. Transplantation, 46, 49s-52s. KRAEL, G., BREEL,M., JANSE,K. & BRUIN, G. (1986), Langerhans cells, veiled cells and interdigitating cells in the mouse recognized by a monoclonal antibody. J. exp. Med., 163, 981-997. MACATONIA,S.E., KNIGHT,S.C., EDWARDS,A.J., GRIFFITHS,S. • FRYER, P. (1987), Localization of antigen on lymph node dendritic cells after exposure to the contact sensitizer fluorescein isothyiocyanate. Functional and morphological studies. J. exp. Med., 166, 1654-1657. MACATONIA,S.E. & KNIGHT,S.C. (1989a), Primary stimulation by dendritic cells induces antiviral proliferative and cytotoxic T~cell responses in vitro. J. exp. Med., 169, 1255-1264. MACATONIA,S.E. & KNIGHT,S.C. (1989b), Dendritic cells and T cells transfer sensitization for delayed-type hypersensitivity after skin-painting with contact sensitizer. J. Immunol., 66, 96-99. ROMANI, N., STINGL,G., TSCHACHLER,E., WITMER,M.D., STEINMAN,R.M., SHEVACH,E.M. & SCHULER, G. (1985), The Thy-l-bcaring cell of murine epidermis: a distinctive leukocyte perhaps related to natural killer cells. J. exp. Med., 161, 1368-1383. SCHULER,G. ~ STEINMAN,R.M. (1985), Murine epidermal Langerhans cells mature into potent immunostimuiatory dendritic cells in vitro. J. exp. Med., 161, 526-546. SILBERBERG,I. (1971), Studies by electron microscopy of epidermis after topical application of mercuric chloride. Morphologic and histochemical findings in epidermal cells of human subjects who do not show allergic sensitivity or primary irritant reactions to mercuric chloride (0.1%). J. invest. Dermatol., 64, 37-51. SILBERBERG-SINAKIN,I., FEDORKO, M.E., BAER, R.L., ROSENTHAL,S.A., BERESOWSKY,V. ~g: THORBECKE,G. (1977), Langerhans cells target cells in immune complex reactions. Cell lmmunoL , 32, 400-416. SILBERBERG-SINAKIN,I., GIGLI,I., BAER,R.L. & THORBECKE,G.T. (1980), Langerhans cells" role in contact hypersensitivity and relationship to lymphoid dendritic cells and macrnrhages. Immunol. Rev., 53, 203-237. SULLIVAN,S., BERGSTRESSER,P.R., TIGELAAR,R.E. & STREILEIN,J.W. (1986), Induction and regulation of contact hypersensitMty by resident, bone-marrow-derived, dendritic epidezmal ceils: Laagerhans cells and Thy-! + epidermal cells. J. Immunol., 137, 2460-2467. THOMAS,D.W., FORNI,G., SHEVACH,E.M. & GREEN,I. (1977), The role of the macrophages as the stimulator cell in contact sensitivity. J. Immunol., 124, 1503-1506. ToEws, G.B., BERGSTRESSER.P.R. & StrEllr:tN, l W (IOr/~), l~pirl~rmal I . . . . . h . . . . . !! ,4~,-. sity determines whether contact sensitivity or unresponsiveness follows skin painting with DNFB. J. Immunol., 124, 445-453. TOWNSEND, A., OHLEN, C., BASTIN, J., LJUNGGREN,H.-G., FOSTER, L. & KARRE, K. (1989), Association of class I major histocompatibility heavy and light chains induced by viral peptides. Nat:~re (Lond.), 340, 443-448. WITMER-PACK, M.D., OLIVIFP~,W., VALINSKY,J., SCHULER, G. ~ STEINMAN, R.M. (1987), Granulocyte/macrophage colony stimulating factor is essential for the viability and function of cultured murine epidermal Langerhans cells. J. exp. Med., 166, 1484-1498.