- Email: [email protected]
T cells, immunosurveillance, and cutaneous immunity
Journal of Dermatological Science 24 Suppl. 1 (2000) S41 – S45 www.elsevier.com/locate/jdermsci
T cells, immunosurveillance, and cutaneous immunity Thomas S. Kupper * Department of Dermatology, Brigham and Women’s Hospital, Har6ard Skin Disease Research Center, Har6ard Medical School, Har6ard Institutes of Medicine, 77 A6enue Louis Pasteur, Boston, MA 02115, USA
Abstract This presentation deals with the key role of the skin in immune function, briefly reviewing what is known about the cell trafficking patterns and molecular events involved in the generation of a specific immune response in the skin. Such information provides a basis for understanding the pathogenesis of autoimmunity-related diseases, and may provide clues to eventual therapeutic approaches. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Immunologic memory; Cell trafficking; Antigen presentation; Dendritic cell; T cell; Autoantigen
1. Introduction Skin is our principle interface with the environment. The skin is charged with protecting the host from the environment for seven decades or more, a challenge that it meets reliably [1]. It has recently become clear that skin is the site at which the immune system first encounters the majority of environmental pathogens [2]. The first encounter provokes the development of memory in the immune system. This element of memory is specific not just for the pathogen, but also for the site where it was encountered (the skin) [1]. Subsequent encounters with the pathogen are met more forcefully by an immune system that has learned about its environment through the acquisition of immunologic memory. * Tel.: +1-617-5255571; fax: + 1-617-5255550. E-mail address: [email protected] (T.S. Kupper).
2. Immunologic memory and T cell receptor diversity Immunologic memory has been appreciated as long as immunology has been a science. Dendritic cells that reside in epithelial tissues that interface with the environment are efficient at internalizing environmental antigens [3]. These dendritic cells mature into potent antigen-presenting cells as they migrate through afferent lymphatics to lymph nodes. Within lymph nodes, they present antigen to naı¨ve T cells [4]. As a result, those T cells specific for the antigen become activated and expand by proliferating, typically more than 1000fold. Part of immunologic memory is therefore a question of cell numbers — after proliferation, the total number of T cells specific for the antigen has increased. Over the next few days, these newly minted memory T cells begin to express new cell surface adhesion molecules and chemokine receptors that allow them to exit vessels in peripheral
0923-1811/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 9 2 3 - 1 8 1 1 ( 0 0 ) 0 0 1 4 0 - 7
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T.S. Kupper / Journal of Dermatological Science 24 (2000) S41–S45
tissues [5]. The pattern of expression of these new molecules depends in part upon the location of the lymph node (see below). Part of memory also involves the expansion and maturation of antigen specific B cells and their soluble products, antibodies. Antibodies, initially IgM and later IgG subclasses, are released into blood and are distributed throughout the body into all tissues. While it is easy to understand how circulating antibodies confer immunologic memory and protect the host, it has been more difficult to understand how specific T cells are able to negotiate the complete terrain of the body so successfully in their search for the antigens for which their Tcr’s are specific. When one analyzes the specifics of what a T cell must accomplish to become activated, this feat becomes even more impressive. T cell receptors are comprised of two chains, most often ab but sometimes gd [6,7]. During intrathymic development, each T cell generates new genes from the a and b loci through recombination and shuffling of different gene segments. Built into this recombination process is some intentional imprecision, so that when segments are joined together a variable number of random nucleotides are added [7]. The result is the generation of trillions of different T cell receptors formed from the pairing of unique ab or gd chains. Since each receptor should have a unique specificity, this endows the immune system with the chance to ‘see’ a nearly unlimited number of antigens. During intrathymic maturation, however, the majority of these T cells are discarded via apoptosis, either because they are autoreactive or because they do not engage MHC molecules sufficiently. Estimates of the diversity of naı¨ve T cells — T cells that have left the thymus but have not yet seen their antigen presented in lymphoid tissue in peripheral blood — suggest that there are roughly a billion different Tcr expressed in the naı¨ve T cell population [8].
3. Trafficking patterns of T cells, dendritic cells and antigens Unlike antibodies, which recognize the three-dimensional structure of glycoproteins, T cell recep-
tors recognize only linear peptides in the context of MHC Class I or II molecules, or hydrophobic non-peptide molecules in the context of CD1 molecules [9]. Only a specialized type of cell — the dendritic cell — can successfully present antigen to naive T cells, a process that involves not only recognition of MHC antigen complex by the T cell, but also costimulation of the T cell via accessory (costimulatory) molecules. Thus, it is critically important to ensure that naı¨ve T cells, dendritic cells, and environmental antigens (including those derived from pathogens) interact frequently and continuously. This goal is achieved by specific and precise trafficking patterns of both T cells, and dendritic cells with the common destination being the lymph node [10]. Lymph nodes concentrate lymph — extracellular fluid — as well as migratory cells (including resident dendritic cells) from large surface areas of epithelium to a single specialized and compact location. Here these dendritic cells, which have matured into potent antigen-presenting cells during this journey, await the arrival of naı¨ve T cells [3,4]. Naı¨ve T cells, however, take a different route to the lymph node. They express on their surface a molecule called L selectin, which tethers (a form of binding that occurs under shear stress) under physiologic blood flow conditions to molecules known as peripheral lymph node addressins (PNAd), expressed uniquely on post-capillary venules within lymph nodes. These T cells, now slowed to a roll by L selectin-PNAd interactions, are activated by a chemokine called ‘secondary lymphoid chemokine’ (SLC) expressed on the surface of this endothelium [11]. By binding of SLC to the lymphocyte receptor CCR7, a Gprotein-coupled chemokine receptor, intracellular signals culminate in the conformational rearrangement of the integrin LFA-1 (CD11a/CD18) [12]. This results in immediate binding to ICAM1, an adhesion molecule also constitutively expressed on lymph node post-capillary venules. This three-step process occurs uniquely in socalled high endothelial venules (HEV) in the lymph node, and is fundamental to the ongoing extravasation of naı¨ve T cells from blood to lymph node. Once in the node, T cells are attracted to dendritic cells by other chemokines,
T.S. Kupper / Journal of Dermatological Science 24 (2000) S41–S45
and the ensuing process leads to frequent sampling of cell surface MHC or CD1 molecules plus antigen by T cell receptors [13]. Most of these interactions are unproductive, and while dendritic cells probably undergo apoptosis in situ, naı¨ve T cells that are not activated leave the node via efferent lymphatics, ultimately re-entering the blood through the thoracic duct. Naı¨ve T cells that do encounter their antigen, appropriately presented, in the lymph node, become activated and proliferate, expanding often more than 1000-fold. When these T cells enter blood via the thoracic duct, they are now memory cells, expressing higher levels of integrins and other adhesion molecules [1,5]. Within the memory T cell genetic program are multiple genes that are upregulated, and some of these appear to be uniquely dependent upon the anatomical location of the lymph node in which the T cell was first activated. For example, within skin-draining lymph nodes, memory T cells express higher levels of PSGL-1, as well as newly induced glycosylating enzymes that decorate PSGL-1 with CD15s-like oligosaccharides [1]. This newly modified form of PSGL-1 is the primary ligand for E selectin in inflamed skin [14]. Recognized by the antibody HECA-452, this PSGL-1 isoform is known as ‘cutaneous lymphocyte antigen’ (CLA). These skin-homing T cells express not only CLA, but also chemokine receptors that can include CC4, CCR6, and CCR10 [1]. The ligands for each of these chemokine receptors can be found in skin. Such skin-homing CLA+T cells enter both normal and inflamed skin, using a distinct three-step process that is initiated by tethering interactions between CLA and E selectin (rather than L selectin PNAd). Memory T cells generated in lymph nodes draining other tissues express different sets of homing molecules; for example, gut homing T cells express high levels of a4b7 integrin, which can initiate tethering and rolling interactions on MAdCAM-1, a non-selectin adhesion molecule expressed preferentially on lamina propria postcapillary venules [5]. It is likely that different chemokine/chemokine receptor interactions are specific for post-capillary venules in this tissue. It is not clear whether a different set of memory T cells mediates homing to inflamed lung [15], but
S43
this possibility would follow by analogy to the situation in skin and gut.
4. Recruitment of memory T cells It is clear that the number of T cell receptor specificities represented in memory T cells in peripheral blood is dramatically lower than that of naı¨ve T cells; that is, there is substantially less diversity. In contrast to the billions of different Tcr in naı¨ve T cells, it is estimated that of the order of 100 000 different specificities are represented within the memory T cell subset [8]. Looked at in another way, this suggests that by adulthood, we have employed only 0.01% of our total T cell repertoire (if we define memory T cells as the only T cells that have seen antigen), and that this is sufficient to endow us with immunocompetence. Because the ratio of naı¨ve to memory T cells is typically 65:35, it also suggests that this tiny fraction of T cells has expanded 1000- to 10 000-fold, in keeping with our prediction. Finally, because CLA+T cells are typically 15% of all T cells (or 35–40% of memory T cells), this suggests that this same percentage of total T cell responses have occurred through the skin over the lifetime of the individual. While this number seems large, it is consistent with the skin’s role as our primary interface with the environment. It also means that cutaneous immunity is a large fraction of total immunity, and is central to our survival. Memory T cells circulate continuously through the body, and probably exit post-capillary venules in peripheral tissue (e.g. skin) constitutively, though not in large numbers. Once in tissue, where they have been recruited by low constitutive levels of E selectin, chemokines, and ICAM-1 on cutaneous post-capillary venules, they are in a position to be activated by dendritic cells within dermis or epidermis that bear antigen in the context of MHC or CD1 molecules [1]. Activation of these T cells leads to release of cytokines. Depending on the cytokines released (e.g. type 1 or type 2), inflammation ensues and additional leukocytes are recruited [16]. The recruitment of memory T cells to skin in general is greatly facili-
S44
T.S. Kupper / Journal of Dermatological Science 24 (2000) S41–S45
tated by inflammation. Inflammation, either via primary cytokines IL-1a,b or TNFa, or mediated by a newly described set of receptors known as Toll-like receptors (Tlrs) that bind bacterial molecules, leads to NFkB-driven enhancement of E selectin, ICAM-1, VCAM-1, and chemokine production [1,17]. Collectively, these molecules enhance the rate and degree to which circulating CLA+ memory T cells are brought into skin. This increases the likelihood that these cells will find their antigen presented by dendritic cells within skin and become activated. The cytokines released by these T cells, and the inflammation they induce, will persist until the antigen is eliminated.
Our new understanding of T cell trafficking allows us to see immunologic memory in a new light. Disease pathogenesis, particularly that of organ-specific autoimmune diseases such as psoriasis, rheumatoid arthritis, asthma, and inflammatory bowel disease, can be viewed as an inaccurate identification by the immune system of a pathogen in the respective organ. Because the presumed pathogen (the autoantigen) can never be eradicated, such diseases are chronic and difficult to control. New therapies that target organ-specific trafficking, and perhaps even T cell receptor specificities within populations of organ-homing memory T cells, may hold the most substantial promise for future intervention.
5. Immune-related disease It is important to recall that the above process evolved to protect the host against infection. Because infection is usually associated with tissue injury, the inflammatory response signals to the acquired immune system (i.e. memory T cells) that an intruder may be present. Because common things occur commonly, it makes sense for the immune system to send its memory T cells to sites of inflammation immediately, so that the intruder can be dealt with swiftly. While this is a highly adaptive and logical host defense pathway, it is subject to considerable dysfunction in disease [1]. For example, in allergic contact dermatitis, the immune system has (incorrectly) identified a contact sensitizer as an intruder, and reproducibly generates exaggerated immune responses on subsequent encounters with these innocuous agents. In atopic dermatitis, the house dust mite has been identified by the immune system as a harmful pathogen. The reason that type 2 cytokines are produced by the antigen-specific CLA+ skin homing T cells in this disease is almost certainly linked to the genetics of atopy, but the rationale for the misguided response is universal. In psoriasis, it is likely that a self-protein expressed in epidermis has been inaccurately identified by the immune system as a foreign pathogen. The type 1 cytokines produced by the specific T cells in psoriasis appear to activate psoriatic skin uniquely, generating the characteristic histopathology of this disease.
Acknowledgements This work was supported by grants from the National Institutes of Health, USA. Presented at the Shiseido Scientific Symposium, Tokyo, Japan 2000.
References [1] Robert C, Kupper TS. Mechanisms of disease: inflammatory skin diseases, T cells, and immune surveillance. New Engl J Med 1999;341:1817 – 28. [2] Fearon DT, Locksley RM. The instructive role of innate immunity in the acquired immune response. Science 1996;272:50 – 3. [3] Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245 – 52. [4] Hart DN. Dendritic cells: unique leukocyte populations which control the primary immune response. Blood 1997;90:3245 – 87. [5] Butcher EC, Picker LJ. Lymphocyte homing and homeostasis. Science 1996;272:60 – 6. [6] Picker LJ, Treer JR, Ferguson-Darnell B, Collins PA, Bergstresser PR, Terstappen LW. Control of lymphocyte recirculation in man. II. Differential regulation of the cutaneous lymphocyte-associated antigen, a tissue-selective homing receptor for skin-homing T cells. J Immunol 1993;150:1122– 36. [7] Davis MM, Bjorkman PJ. T-cell antigen receptor genes and T-cell recognition. Nature 1988;334:395 – 402 published erratum appears in Nature (1988) 335(6192), 744. [8] Arstila TP, Casrouge A, Baron VJE, Kanellopoulos J, Kourilsky P. A direct estimate of the human ab T cell receptor diversity. Science 1999;286:958 – 61.
T.S. Kupper / Journal of Dermatological Science 24 (2000) S41–S45 [9] Porcelli SA, Modlin RL. The CD1 system: antigen-presenting molecules for T cell recognition of lipids and glycolipids. Annu Rev Immunol 1999;17:297–329. [10] Cyster JD. Chemokines and cell migration in secondary lymphoid organs. Science 1999;286:2098–102. [11] Warnock RA, Askari S, Butcher EC, von Andrian UH. Molecular mechanisms of lymphocyte homing to peripheral lymph nodes. J Exp Med 1998;187:205–16. [12] Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994;76:301 – 14. [13] Lanzavecchia A. Mechanisms of antigen uptake for presentation. Curr Opin Immunol 1996;8:348–54. [14] Fuhlbrigge RC, Kieffer JD, Armerding D, Kupper TS.
.
S45
Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells. Nature 1997;389:978 – 81. [15] Picker LJ, Martin RJ, Trumble A, Newman LS, Collins PA, Bergstresser PR, Leung DY. Differential expression of lymphocyte homing receptors by human memory/effector T cells in pulmonary versus cutaneous immune effector sites. Eur J Immunol 1994;24:1269 – 77. [16] O’Garra A. Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 1998;8:275 – 83. [17] Barnes PJ, Karin M. Nuclear factor-kB: a pivotal transcription factor in chronic inflammatory diseases. New Engl J Med 1997;336:1066 – 71.
T cells, immunosurveillance, and cutaneous immunity Thomas S. Kupper * Department of Dermatology, Brigham and Women’s Hospital, Har6ard Skin Disease Research Center, Har6ard Medical School, Har6ard Institutes of Medicine, 77 A6enue Louis Pasteur, Boston, MA 02115, USA
Abstract This presentation deals with the key role of the skin in immune function, briefly reviewing what is known about the cell trafficking patterns and molecular events involved in the generation of a specific immune response in the skin. Such information provides a basis for understanding the pathogenesis of autoimmunity-related diseases, and may provide clues to eventual therapeutic approaches. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Immunologic memory; Cell trafficking; Antigen presentation; Dendritic cell; T cell; Autoantigen
1. Introduction Skin is our principle interface with the environment. The skin is charged with protecting the host from the environment for seven decades or more, a challenge that it meets reliably [1]. It has recently become clear that skin is the site at which the immune system first encounters the majority of environmental pathogens [2]. The first encounter provokes the development of memory in the immune system. This element of memory is specific not just for the pathogen, but also for the site where it was encountered (the skin) [1]. Subsequent encounters with the pathogen are met more forcefully by an immune system that has learned about its environment through the acquisition of immunologic memory. * Tel.: +1-617-5255571; fax: + 1-617-5255550. E-mail address: [email protected] (T.S. Kupper).
2. Immunologic memory and T cell receptor diversity Immunologic memory has been appreciated as long as immunology has been a science. Dendritic cells that reside in epithelial tissues that interface with the environment are efficient at internalizing environmental antigens [3]. These dendritic cells mature into potent antigen-presenting cells as they migrate through afferent lymphatics to lymph nodes. Within lymph nodes, they present antigen to naı¨ve T cells [4]. As a result, those T cells specific for the antigen become activated and expand by proliferating, typically more than 1000fold. Part of immunologic memory is therefore a question of cell numbers — after proliferation, the total number of T cells specific for the antigen has increased. Over the next few days, these newly minted memory T cells begin to express new cell surface adhesion molecules and chemokine receptors that allow them to exit vessels in peripheral
0923-1811/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 9 2 3 - 1 8 1 1 ( 0 0 ) 0 0 1 4 0 - 7
S42
T.S. Kupper / Journal of Dermatological Science 24 (2000) S41–S45
tissues [5]. The pattern of expression of these new molecules depends in part upon the location of the lymph node (see below). Part of memory also involves the expansion and maturation of antigen specific B cells and their soluble products, antibodies. Antibodies, initially IgM and later IgG subclasses, are released into blood and are distributed throughout the body into all tissues. While it is easy to understand how circulating antibodies confer immunologic memory and protect the host, it has been more difficult to understand how specific T cells are able to negotiate the complete terrain of the body so successfully in their search for the antigens for which their Tcr’s are specific. When one analyzes the specifics of what a T cell must accomplish to become activated, this feat becomes even more impressive. T cell receptors are comprised of two chains, most often ab but sometimes gd [6,7]. During intrathymic development, each T cell generates new genes from the a and b loci through recombination and shuffling of different gene segments. Built into this recombination process is some intentional imprecision, so that when segments are joined together a variable number of random nucleotides are added [7]. The result is the generation of trillions of different T cell receptors formed from the pairing of unique ab or gd chains. Since each receptor should have a unique specificity, this endows the immune system with the chance to ‘see’ a nearly unlimited number of antigens. During intrathymic maturation, however, the majority of these T cells are discarded via apoptosis, either because they are autoreactive or because they do not engage MHC molecules sufficiently. Estimates of the diversity of naı¨ve T cells — T cells that have left the thymus but have not yet seen their antigen presented in lymphoid tissue in peripheral blood — suggest that there are roughly a billion different Tcr expressed in the naı¨ve T cell population [8].
3. Trafficking patterns of T cells, dendritic cells and antigens Unlike antibodies, which recognize the three-dimensional structure of glycoproteins, T cell recep-
tors recognize only linear peptides in the context of MHC Class I or II molecules, or hydrophobic non-peptide molecules in the context of CD1 molecules [9]. Only a specialized type of cell — the dendritic cell — can successfully present antigen to naive T cells, a process that involves not only recognition of MHC antigen complex by the T cell, but also costimulation of the T cell via accessory (costimulatory) molecules. Thus, it is critically important to ensure that naı¨ve T cells, dendritic cells, and environmental antigens (including those derived from pathogens) interact frequently and continuously. This goal is achieved by specific and precise trafficking patterns of both T cells, and dendritic cells with the common destination being the lymph node [10]. Lymph nodes concentrate lymph — extracellular fluid — as well as migratory cells (including resident dendritic cells) from large surface areas of epithelium to a single specialized and compact location. Here these dendritic cells, which have matured into potent antigen-presenting cells during this journey, await the arrival of naı¨ve T cells [3,4]. Naı¨ve T cells, however, take a different route to the lymph node. They express on their surface a molecule called L selectin, which tethers (a form of binding that occurs under shear stress) under physiologic blood flow conditions to molecules known as peripheral lymph node addressins (PNAd), expressed uniquely on post-capillary venules within lymph nodes. These T cells, now slowed to a roll by L selectin-PNAd interactions, are activated by a chemokine called ‘secondary lymphoid chemokine’ (SLC) expressed on the surface of this endothelium [11]. By binding of SLC to the lymphocyte receptor CCR7, a Gprotein-coupled chemokine receptor, intracellular signals culminate in the conformational rearrangement of the integrin LFA-1 (CD11a/CD18) [12]. This results in immediate binding to ICAM1, an adhesion molecule also constitutively expressed on lymph node post-capillary venules. This three-step process occurs uniquely in socalled high endothelial venules (HEV) in the lymph node, and is fundamental to the ongoing extravasation of naı¨ve T cells from blood to lymph node. Once in the node, T cells are attracted to dendritic cells by other chemokines,
T.S. Kupper / Journal of Dermatological Science 24 (2000) S41–S45
and the ensuing process leads to frequent sampling of cell surface MHC or CD1 molecules plus antigen by T cell receptors [13]. Most of these interactions are unproductive, and while dendritic cells probably undergo apoptosis in situ, naı¨ve T cells that are not activated leave the node via efferent lymphatics, ultimately re-entering the blood through the thoracic duct. Naı¨ve T cells that do encounter their antigen, appropriately presented, in the lymph node, become activated and proliferate, expanding often more than 1000-fold. When these T cells enter blood via the thoracic duct, they are now memory cells, expressing higher levels of integrins and other adhesion molecules [1,5]. Within the memory T cell genetic program are multiple genes that are upregulated, and some of these appear to be uniquely dependent upon the anatomical location of the lymph node in which the T cell was first activated. For example, within skin-draining lymph nodes, memory T cells express higher levels of PSGL-1, as well as newly induced glycosylating enzymes that decorate PSGL-1 with CD15s-like oligosaccharides [1]. This newly modified form of PSGL-1 is the primary ligand for E selectin in inflamed skin [14]. Recognized by the antibody HECA-452, this PSGL-1 isoform is known as ‘cutaneous lymphocyte antigen’ (CLA). These skin-homing T cells express not only CLA, but also chemokine receptors that can include CC4, CCR6, and CCR10 [1]. The ligands for each of these chemokine receptors can be found in skin. Such skin-homing CLA+T cells enter both normal and inflamed skin, using a distinct three-step process that is initiated by tethering interactions between CLA and E selectin (rather than L selectin PNAd). Memory T cells generated in lymph nodes draining other tissues express different sets of homing molecules; for example, gut homing T cells express high levels of a4b7 integrin, which can initiate tethering and rolling interactions on MAdCAM-1, a non-selectin adhesion molecule expressed preferentially on lamina propria postcapillary venules [5]. It is likely that different chemokine/chemokine receptor interactions are specific for post-capillary venules in this tissue. It is not clear whether a different set of memory T cells mediates homing to inflamed lung [15], but
S43
this possibility would follow by analogy to the situation in skin and gut.
4. Recruitment of memory T cells It is clear that the number of T cell receptor specificities represented in memory T cells in peripheral blood is dramatically lower than that of naı¨ve T cells; that is, there is substantially less diversity. In contrast to the billions of different Tcr in naı¨ve T cells, it is estimated that of the order of 100 000 different specificities are represented within the memory T cell subset [8]. Looked at in another way, this suggests that by adulthood, we have employed only 0.01% of our total T cell repertoire (if we define memory T cells as the only T cells that have seen antigen), and that this is sufficient to endow us with immunocompetence. Because the ratio of naı¨ve to memory T cells is typically 65:35, it also suggests that this tiny fraction of T cells has expanded 1000- to 10 000-fold, in keeping with our prediction. Finally, because CLA+T cells are typically 15% of all T cells (or 35–40% of memory T cells), this suggests that this same percentage of total T cell responses have occurred through the skin over the lifetime of the individual. While this number seems large, it is consistent with the skin’s role as our primary interface with the environment. It also means that cutaneous immunity is a large fraction of total immunity, and is central to our survival. Memory T cells circulate continuously through the body, and probably exit post-capillary venules in peripheral tissue (e.g. skin) constitutively, though not in large numbers. Once in tissue, where they have been recruited by low constitutive levels of E selectin, chemokines, and ICAM-1 on cutaneous post-capillary venules, they are in a position to be activated by dendritic cells within dermis or epidermis that bear antigen in the context of MHC or CD1 molecules [1]. Activation of these T cells leads to release of cytokines. Depending on the cytokines released (e.g. type 1 or type 2), inflammation ensues and additional leukocytes are recruited [16]. The recruitment of memory T cells to skin in general is greatly facili-
S44
T.S. Kupper / Journal of Dermatological Science 24 (2000) S41–S45
tated by inflammation. Inflammation, either via primary cytokines IL-1a,b or TNFa, or mediated by a newly described set of receptors known as Toll-like receptors (Tlrs) that bind bacterial molecules, leads to NFkB-driven enhancement of E selectin, ICAM-1, VCAM-1, and chemokine production [1,17]. Collectively, these molecules enhance the rate and degree to which circulating CLA+ memory T cells are brought into skin. This increases the likelihood that these cells will find their antigen presented by dendritic cells within skin and become activated. The cytokines released by these T cells, and the inflammation they induce, will persist until the antigen is eliminated.
Our new understanding of T cell trafficking allows us to see immunologic memory in a new light. Disease pathogenesis, particularly that of organ-specific autoimmune diseases such as psoriasis, rheumatoid arthritis, asthma, and inflammatory bowel disease, can be viewed as an inaccurate identification by the immune system of a pathogen in the respective organ. Because the presumed pathogen (the autoantigen) can never be eradicated, such diseases are chronic and difficult to control. New therapies that target organ-specific trafficking, and perhaps even T cell receptor specificities within populations of organ-homing memory T cells, may hold the most substantial promise for future intervention.
5. Immune-related disease It is important to recall that the above process evolved to protect the host against infection. Because infection is usually associated with tissue injury, the inflammatory response signals to the acquired immune system (i.e. memory T cells) that an intruder may be present. Because common things occur commonly, it makes sense for the immune system to send its memory T cells to sites of inflammation immediately, so that the intruder can be dealt with swiftly. While this is a highly adaptive and logical host defense pathway, it is subject to considerable dysfunction in disease [1]. For example, in allergic contact dermatitis, the immune system has (incorrectly) identified a contact sensitizer as an intruder, and reproducibly generates exaggerated immune responses on subsequent encounters with these innocuous agents. In atopic dermatitis, the house dust mite has been identified by the immune system as a harmful pathogen. The reason that type 2 cytokines are produced by the antigen-specific CLA+ skin homing T cells in this disease is almost certainly linked to the genetics of atopy, but the rationale for the misguided response is universal. In psoriasis, it is likely that a self-protein expressed in epidermis has been inaccurately identified by the immune system as a foreign pathogen. The type 1 cytokines produced by the specific T cells in psoriasis appear to activate psoriatic skin uniquely, generating the characteristic histopathology of this disease.
Acknowledgements This work was supported by grants from the National Institutes of Health, USA. Presented at the Shiseido Scientific Symposium, Tokyo, Japan 2000.
References [1] Robert C, Kupper TS. Mechanisms of disease: inflammatory skin diseases, T cells, and immune surveillance. New Engl J Med 1999;341:1817 – 28. [2] Fearon DT, Locksley RM. The instructive role of innate immunity in the acquired immune response. Science 1996;272:50 – 3. [3] Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245 – 52. [4] Hart DN. Dendritic cells: unique leukocyte populations which control the primary immune response. Blood 1997;90:3245 – 87. [5] Butcher EC, Picker LJ. Lymphocyte homing and homeostasis. Science 1996;272:60 – 6. [6] Picker LJ, Treer JR, Ferguson-Darnell B, Collins PA, Bergstresser PR, Terstappen LW. Control of lymphocyte recirculation in man. II. Differential regulation of the cutaneous lymphocyte-associated antigen, a tissue-selective homing receptor for skin-homing T cells. J Immunol 1993;150:1122– 36. [7] Davis MM, Bjorkman PJ. T-cell antigen receptor genes and T-cell recognition. Nature 1988;334:395 – 402 published erratum appears in Nature (1988) 335(6192), 744. [8] Arstila TP, Casrouge A, Baron VJE, Kanellopoulos J, Kourilsky P. A direct estimate of the human ab T cell receptor diversity. Science 1999;286:958 – 61.
T.S. Kupper / Journal of Dermatological Science 24 (2000) S41–S45 [9] Porcelli SA, Modlin RL. The CD1 system: antigen-presenting molecules for T cell recognition of lipids and glycolipids. Annu Rev Immunol 1999;17:297–329. [10] Cyster JD. Chemokines and cell migration in secondary lymphoid organs. Science 1999;286:2098–102. [11] Warnock RA, Askari S, Butcher EC, von Andrian UH. Molecular mechanisms of lymphocyte homing to peripheral lymph nodes. J Exp Med 1998;187:205–16. [12] Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994;76:301 – 14. [13] Lanzavecchia A. Mechanisms of antigen uptake for presentation. Curr Opin Immunol 1996;8:348–54. [14] Fuhlbrigge RC, Kieffer JD, Armerding D, Kupper TS.
.
S45
Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells. Nature 1997;389:978 – 81. [15] Picker LJ, Martin RJ, Trumble A, Newman LS, Collins PA, Bergstresser PR, Leung DY. Differential expression of lymphocyte homing receptors by human memory/effector T cells in pulmonary versus cutaneous immune effector sites. Eur J Immunol 1994;24:1269 – 77. [16] O’Garra A. Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 1998;8:275 – 83. [17] Barnes PJ, Karin M. Nuclear factor-kB: a pivotal transcription factor in chronic inflammatory diseases. New Engl J Med 1997;336:1066 – 71.