Immunological Reviews 1990, No. 117 Published by Munksgaard, Copenhagen, Denmark No part may be reproduced by any process without written permission from the author(s)
Functional Dichotomy between Langerhans Cells that Present Antigen to Naive and to Memory/Effector T Lymphocytes J. WAYNE STREILEIN, SUSAN R GRAMMER, TAKESHI YOSHIKAWA, AiCHA DEMIDEM & MARTIN VERMEER
INTRODUCTION
The notion that lymphocytes, especially T lymphocytes, require the assistance of other cell types in order to recognize antigens was born in the 1960s. Experiments utilizing peritoneal macrophages and splenic adherent cells confirmed that "accessory" cells were needed in order to "prepare" antigen for T cells - although at the time virtually nothing was known concerning the nature of the "preparation". Because other T cells were unable to provide this accessory function and B cells were less capable than macrophages, it was concluded that macrophages were the important "accessory" cells - or, to use a more contemporary term - the important antigen-presenting cells. Since the majority of immunologists in the 1960s and early 1970s used the spleen as the source of lymphoid cells for study, and since this organ can readily provide T and B lymphocytes, as well as adherent cells (i.e. macrophages), the principal rules of antigen presentation were established with cells from this organ. Innocently enough, this experimental approach led workers in the field to believe that antigen processing and presentation are inductive immune events that typically take place in organized lymphoid tissues - such as spleen and lymph nodes. It was assumed that sensitization to an exogenous antigen was dependent upon the ability of antigenic molecules to gain access, in some manner or other, to a lymphoid organ. Consequently, many investigators were not prepared for the seminal interpretDepartment of Microbiology and Immunology, (R-138), University of Miami School of Medicine, P.O. Box 016960, Miami, Florida 33101, U.S.A. Telephone (305) 547-6655/6694, Fax (305) 548-4623.
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ation of histopathologic observations on epidermal Langerhans cells made by Silberberg and her colleagues (1973), nor for the results of the original in vitro studies of antigen presentation by epidermally-derived Langerhans cells, conducted by Stingl and his many collaborators (1978). Based on the dogma extant at the time, there did not appear to be a "need" for antigen-presenting cells in non-lymphoid tissues, such as skin. Nor was it clear whether an antigen-presenting cell could function in such an environment. Yet, studies conducted in the early 1980s pointed unequivocally to an important in vivo role for Langerhans cells within the epidermis (Toews et al. 1980, Streilein et al. 1980). Experimental immunology in the past decade has focussed much of its attention on the identification and description of cytokines and their receptors (reviewed by Balkwill & Burke 1989). These molecules mediated in large measure the intercellular communications which provide the immune system with its functional integration. During induction and expression of immunity, lymphocytes and antigen-presenting cells signal each other in an enormously complicated, yet carefully orchestrated, network of exchanged lymphokines and monokines. Through their capacity selectively to activate or inactivate specific cell functions, cytokines are thought to be the primary mediators of up- and down-regulation of the immune response. Experimental immunology is not alone in its enthusiastic study of cytokines. It is now apparent that many (although certainly not all) of the cytokines and receptors that have been found to participate in intercellular communication among cells of the immune system can play signalling roles among other types of cells and, indeed, in non-lymphoid tissues of the body. Cytokines such as IL1, tumor-necrosis factor-alpha (TNFj), and alpha interferon are known to be synthesized and secreted by many different cell types. Moreover, receptors for these cytokines can be expressed on a variety of cells and tissues. Most cells and tissues develop, differentiate and remain fixed at a particular body site throughout life (for example - liver, skin, brain). By contrast, bone marrow-derived cells exhibit the opposite behavior. Blood leukocytes in general, and lymphocytes and monocytes in particular, regularly migrate from one site in the body to another. Given the extensive number of cytokines that exist, and the overlap in target cell types upon which individual cytokines can act, the potential is great for cytokines secreted by a fixed tissue cell to infiuence the functional properties of migratory cells that happen to enter the former's domain. The term "regional sphere of infiuence" has been used (Streilein 1988b) to designate tissuespecific environments that are dominated by a particular differentiated cell type whose infiuence, mediated in part through cytokine release, creates an "appropriate" microenvironment for that tissue. For example, keratinocytes, the parenchymal cells of skin, create - in part via the cytokines they release - a microenvironment in the epidermis that sustains the proliferation of stem cells in the basilar layer, and yet promotes the progressive differentiation of basal cells as they slowly
LANGERHANS CELL ACTIVATION OF T CELLS
161
rise to become the corneocytes of the cutaneous surface. Lymphoid organs also develop and maintain unique microenvironments that promote the proliferative and differentiative functions of T and B lymphocytes. Although different types of cytokine-secreting cells exist in lymph nodes and spleens, T lymphocytes appear to play the dominant role in creating the unique microenvironments found within these organized lymphoid tissues. The ideas to he developed in this review are that (a) Langerhans cells are highly specialized antigen-processing and -presenting cells whose primary function is to present antigen to, and thereby activate, T lymphocytes; (b) Langerhans cells exist in two functionally distinct forms which equip the cells differentially to present antigen to primed, memory T cells or to unprimed, antigen-specific T cells, and (c) the differences between the two functionally distinct forms of Langerhans cells are dictated by the microenvironment in which they present antigen to T cells. As a measure of these ideas, a hypothesis is explored which suggests that psoriasis is a disorder resulting from the inappropriate imposition upon the skin of a cytokine-mediated microenvironment dictated by T cells. EPIDERMAL LANGERHANS CELLS ARE THE IMPORTANT ANTIGENPRESENTING CELLS OF SKIN Langerhans cells in induction of cutaneous immunity In vitro studies of epidermal Langerhans cells, which revealed that these cells could function as antigen-presenting cells (Stingl et al. 1978), are extensively documented in other articles within this volume, and will not be presented here. It has been more difficult to demonstrate in vivo antigen-presenting properties of Langerhans cells because the evidence, though convincing, tends to be circumstantial. Investigators have taken advantage of cutaneous surfaces that are physiologically deprived, or experimentally depleted, of normal Langerhans cells (Bergstresser et al. 1980). Contact hypersensitivity (CH) to highly reactive haptens, such as dinitrofiuorobenzene (DNFB), oxazolone, and fluorescein isothiocyanate (FITC), develops if the hapten is painted on normal body wall skin in mice, rats, hamster, guinea pigs, and humans. However, CH fails to develop if the hapten is painted on mouse tail skin (Toews et al. 1980), hamster cheek pouch (Streilein & Bergstresser 1981), or skin exposed to low doses of ultraviolet B (UVB) light (Streilein et al. 1982). In all of these cases, the density of normal Langerhans cells in the epidermis at the time of hapten application is markedly reduced from normal (
Functional Dichotomy between Langerhans Cells that Present Antigen to Naive and to Memory/Effector T Lymphocytes J. WAYNE STREILEIN, SUSAN R GRAMMER, TAKESHI YOSHIKAWA, AiCHA DEMIDEM & MARTIN VERMEER
INTRODUCTION
The notion that lymphocytes, especially T lymphocytes, require the assistance of other cell types in order to recognize antigens was born in the 1960s. Experiments utilizing peritoneal macrophages and splenic adherent cells confirmed that "accessory" cells were needed in order to "prepare" antigen for T cells - although at the time virtually nothing was known concerning the nature of the "preparation". Because other T cells were unable to provide this accessory function and B cells were less capable than macrophages, it was concluded that macrophages were the important "accessory" cells - or, to use a more contemporary term - the important antigen-presenting cells. Since the majority of immunologists in the 1960s and early 1970s used the spleen as the source of lymphoid cells for study, and since this organ can readily provide T and B lymphocytes, as well as adherent cells (i.e. macrophages), the principal rules of antigen presentation were established with cells from this organ. Innocently enough, this experimental approach led workers in the field to believe that antigen processing and presentation are inductive immune events that typically take place in organized lymphoid tissues - such as spleen and lymph nodes. It was assumed that sensitization to an exogenous antigen was dependent upon the ability of antigenic molecules to gain access, in some manner or other, to a lymphoid organ. Consequently, many investigators were not prepared for the seminal interpretDepartment of Microbiology and Immunology, (R-138), University of Miami School of Medicine, P.O. Box 016960, Miami, Florida 33101, U.S.A. Telephone (305) 547-6655/6694, Fax (305) 548-4623.
160
STREILEIN ET AL.
ation of histopathologic observations on epidermal Langerhans cells made by Silberberg and her colleagues (1973), nor for the results of the original in vitro studies of antigen presentation by epidermally-derived Langerhans cells, conducted by Stingl and his many collaborators (1978). Based on the dogma extant at the time, there did not appear to be a "need" for antigen-presenting cells in non-lymphoid tissues, such as skin. Nor was it clear whether an antigen-presenting cell could function in such an environment. Yet, studies conducted in the early 1980s pointed unequivocally to an important in vivo role for Langerhans cells within the epidermis (Toews et al. 1980, Streilein et al. 1980). Experimental immunology in the past decade has focussed much of its attention on the identification and description of cytokines and their receptors (reviewed by Balkwill & Burke 1989). These molecules mediated in large measure the intercellular communications which provide the immune system with its functional integration. During induction and expression of immunity, lymphocytes and antigen-presenting cells signal each other in an enormously complicated, yet carefully orchestrated, network of exchanged lymphokines and monokines. Through their capacity selectively to activate or inactivate specific cell functions, cytokines are thought to be the primary mediators of up- and down-regulation of the immune response. Experimental immunology is not alone in its enthusiastic study of cytokines. It is now apparent that many (although certainly not all) of the cytokines and receptors that have been found to participate in intercellular communication among cells of the immune system can play signalling roles among other types of cells and, indeed, in non-lymphoid tissues of the body. Cytokines such as IL1, tumor-necrosis factor-alpha (TNFj), and alpha interferon are known to be synthesized and secreted by many different cell types. Moreover, receptors for these cytokines can be expressed on a variety of cells and tissues. Most cells and tissues develop, differentiate and remain fixed at a particular body site throughout life (for example - liver, skin, brain). By contrast, bone marrow-derived cells exhibit the opposite behavior. Blood leukocytes in general, and lymphocytes and monocytes in particular, regularly migrate from one site in the body to another. Given the extensive number of cytokines that exist, and the overlap in target cell types upon which individual cytokines can act, the potential is great for cytokines secreted by a fixed tissue cell to infiuence the functional properties of migratory cells that happen to enter the former's domain. The term "regional sphere of infiuence" has been used (Streilein 1988b) to designate tissuespecific environments that are dominated by a particular differentiated cell type whose infiuence, mediated in part through cytokine release, creates an "appropriate" microenvironment for that tissue. For example, keratinocytes, the parenchymal cells of skin, create - in part via the cytokines they release - a microenvironment in the epidermis that sustains the proliferation of stem cells in the basilar layer, and yet promotes the progressive differentiation of basal cells as they slowly
LANGERHANS CELL ACTIVATION OF T CELLS
161
rise to become the corneocytes of the cutaneous surface. Lymphoid organs also develop and maintain unique microenvironments that promote the proliferative and differentiative functions of T and B lymphocytes. Although different types of cytokine-secreting cells exist in lymph nodes and spleens, T lymphocytes appear to play the dominant role in creating the unique microenvironments found within these organized lymphoid tissues. The ideas to he developed in this review are that (a) Langerhans cells are highly specialized antigen-processing and -presenting cells whose primary function is to present antigen to, and thereby activate, T lymphocytes; (b) Langerhans cells exist in two functionally distinct forms which equip the cells differentially to present antigen to primed, memory T cells or to unprimed, antigen-specific T cells, and (c) the differences between the two functionally distinct forms of Langerhans cells are dictated by the microenvironment in which they present antigen to T cells. As a measure of these ideas, a hypothesis is explored which suggests that psoriasis is a disorder resulting from the inappropriate imposition upon the skin of a cytokine-mediated microenvironment dictated by T cells. EPIDERMAL LANGERHANS CELLS ARE THE IMPORTANT ANTIGENPRESENTING CELLS OF SKIN Langerhans cells in induction of cutaneous immunity In vitro studies of epidermal Langerhans cells, which revealed that these cells could function as antigen-presenting cells (Stingl et al. 1978), are extensively documented in other articles within this volume, and will not be presented here. It has been more difficult to demonstrate in vivo antigen-presenting properties of Langerhans cells because the evidence, though convincing, tends to be circumstantial. Investigators have taken advantage of cutaneous surfaces that are physiologically deprived, or experimentally depleted, of normal Langerhans cells (Bergstresser et al. 1980). Contact hypersensitivity (CH) to highly reactive haptens, such as dinitrofiuorobenzene (DNFB), oxazolone, and fluorescein isothiocyanate (FITC), develops if the hapten is painted on normal body wall skin in mice, rats, hamster, guinea pigs, and humans. However, CH fails to develop if the hapten is painted on mouse tail skin (Toews et al. 1980), hamster cheek pouch (Streilein & Bergstresser 1981), or skin exposed to low doses of ultraviolet B (UVB) light (Streilein et al. 1982). In all of these cases, the density of normal Langerhans cells in the epidermis at the time of hapten application is markedly reduced from normal (
