The Lamina Propria: a Dynamic, Complex Mucosal Compartment An Overview STEPHAN R. TARGAN Department of Medicine Division of Gastroenterology University of California, Los Angeles Los Angeles, California 90024-1786
INTRODUCTION The lamina propria is the layer of the intestinal wall which lies between the epithelium and the muscularis mucosae. The lamina propria has unique immune properties, and functions as a component of the mucosal immune system. Therefore, this paper provides a description of the lamina propria within the context of the encompassing mucosal immune system.'q2 The nature and interaction of the many cell types present within the lamina propria are described. This complement of cells undergo a perpetual process of activation, migration and homing to effect an environmental defense. Comprehension of cellular trafficking to this compartment will permit insight into the interaction between lamina propria cells and the resident endothelial cells, fibroblasts, smooth muscle cells and epithelial cells which exquisitely regulate the immune response.
The Mucosal Immune System The mucosal-associated lymphoid tissue (MALT) (FIG.1) represents a unique immune compartment with distinct characteristic^.^ Primary mucosal responses are initiated yet systemic responses are suppressed in the MALT. Due to its proximity to the host's environmental interface, the MALT is the initial line of immune defense for the host's interaction with its environment. This tissue has evolved to balance two opposing environmental pressures. First, the MALT provides protection to the host from invading organisms from the outside environment. Secondly, the MALT induces immune tolerance to numerous harmless environmental antigens so that the immune system does not become overwhelmed and indirectly injure the host. The balance between these two potentially conflicting responses is maintained by a system of exquisite regulat i ~ n . ' - * The * ~ lamina propria is located subepithelially within the intestinal wall. Typically, 'inflammatory cells' exist within the mucosa; therefore, an inflammatory infiltrate is normally present in the lamina propria. Cells within the lamina propria appear to migrate from other areas or are generated locally, and both can be induced to differentiate by local environmental factors. The functioning mucosal structure can be divided into afferent and efferent limbs (FIG. 2).5-7 Within the afferent limb are the specialized areas of the intestine in which lymphocytes of both B and T cell phenotypes as well as 61
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ANNALS NEW YORK ACADEMY OF SCIENCES
FIGURE 1. Diagram of the common mucosal-associated lymphoid tissues (MALT). Shows dissemination of effector cells from an intestinally-generated immune response throughout the entire MALT. (Reprinted by permission from the Journal of Allergy and Clinical Immunology.)
macrophages are aggregated; referred to as lymphoid aggregates, or Peyer's patches. A specialized intestinal epithelium (comprised of membranous M cells) stretches over the domes of these lymphoid aggregates.*-" These cells are capable of sampling antigens from the intestinal environment; both viable particulate antigens as well as soluble antigens are bound to these cells.9 In addition to local lymphoid follicles, there are differences in the lamina propria cell types within different regions of the gastrointestinal tract. In the colon and in the ileum, there appears to be an increased number of organized lymphoid follicles compared to the more proximal intestine.2 Physiologically this may be so that antigen sampling of the environment may occur in areas where absorbed antigens have been removed. There are two distinct compartments within the efferent limb of the mucosa: the lamina propria and the intraepithelial compartment (see FIG. 2). The nonorganized, efferent area of the lamina propria (FIG.2) consists of multiple cell types, capable of inflammatory responses (many of which will be discussed in detail in subsequent papers). These include T and B lymphocytes, macrophages, neutrophils, eosinophils, mast cells, endothelial cells, tissue fibroblasts, smooth muscle cells, and epithelial cells. The proximity of these cells to each other provides for multiple potential interactions among cell types. The fact that most T cells within the lamina propria are activated and are of the memory phenotype12v13 make this compartment one in which there are higher levels of inducible
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63
cytokines as compared to other immune compartments. l4 Overlying these cells within the epithelium are the intraepithelial lymphocytes. The intraepithelial compartment consists mainly of unique T cells with very few, if any B cell^.^^-*^ The nature of the T cell receptors on these cells varies depending upon the species. In rodents the majority of the intraepithelial T cells express T-yi3.I6 In humans, the vast majority of the T cells are T-aP.*O Most of these are of the CD8+ phenotype. The cells are cytotoxic and can release c y t ~ k i n e s . ' ~ The -'~ intraepithelial lymphocytes respond to signals through different receptors than systemic T cells in that they do not respond through the T cell receptor but can be activated through the CD2 accessory pathway.*' Recently, it has been suggested that these cells could become autoreactive, particularly responding to non-MHC antigens expressed on epithelial cells (Kronenberg M, personal communication). The dynamic structure of the lamina propria, as well as intraepithelial lymphocyte compartment is unique, in that there are large numbers of inflammatory cells which have the potential to not only protect the host but also injure it, Therefore, tight regulation of these agents of destruction is critical for host survival.
AFFERENT
EFFERENT
ANTIGEN
THORACIC DUCT
FIGURE 2. Schematic representation of the structure and movement of the afferent and efferent circuits of the mucosal immune compartment. IEL = intraepithelial lymphocyte; MLN = mesenteric lymph node. (Reprinted by permission from the Annals oflnternal Medicine.)
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Lamina Propria: Important Control Points Traficking
Vital to understanding of the lamina propria as an immune compartment is definition of the mechanisms that regulate its dynamic characteristics. FIGURE 3 depicts the cellular trafficking patterns following a response to an environmental antigen. The antigen is expressed by specialized cells (Mcells) within the epithelium that overlay Peyer’s patches.I4 The antigen is transported into the mucosa where macrophages pinocytose, process and re-express the antigen on their cell
FIGURE 3. Repertoire of cells and soluble mediators in the lamina propria primed for inflammatory responses.
surfaces in association with major histocompatibility complex molecules. This aggregate then induces both T and B cell responses by triggering cell activation and selected cytokine release (ILl, TGFB, IL6, IL5) within the Peyer’s patches. These cytokines participate in altering the production by mucosal B cells of immunoglobulin to the IgA isotype that predominates in the intestinal secretions within the mucosa.22-26 Following activation and differentiation, T and/or B cells migrate from the Peyer’s patch. The signalling process that induces migration, however, remains to be defined. The cells migrate to the mesenteric lymph nodes where further activation and production of responsive clones occurs. The blast cells then traffic through the thoracic duct back into the circulation and by specific ligand-
65
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ligand interaction^^'-^^ bind to and then cross the endothelium, thereby homing specifically to the lamina p r ~ p r i a . ~ ~ The regulation of cell surface glycoproteins and receptors in both circulating effector cells and endothelial cells plays the key role determining the trafficking of lymphocytes and neutrophils into the lamina p r ~ p r i a . ’ ~It. ~appears ~ as though expression of glycoproteins and receptors is induced by inflammatory cytokines and therefore trafficking patterns of cells to the lamina propria can be altered by providing chemotactic signals as well as by enhancing expression of ligands and receptor^.^^.^* Arachidonic acid products and T cell- and fibroblast-associated cytokines such as IL-8 which induce expression of ELAMs, ICAMs, or VLAMs on endothelial cells are chemotactic for n e ~ t r o p h i l sOnce . ~ ~ circulating cells are bound by these ligands, other ligand interactions promote movement through the endothelium within the lamina p r ~ p r i a . ~ ’ , ~The ~ , ~phenomenon ’ of CD8 T cell migration from the lamina propria into the intraepithelium is not clearly understood. This homing process allows a wide dissemination of an isolated response to exogenous antigen. For example, a response generated in the ileum may send specific antigen responsive cells to the rest of the small intestine, the colon, lung and salivary glands. What determines the extent of dissemination also remains undefined.
+
Signals
The lamina propria cells respond to different signals than the cells from other immune compartments. For example, in the systemic immune system T cell responses are preferentially driven through the T cell receptor. In contrast, the lamina propria T cell responds best when signalling occurs via alternate pathways and auxiliary molecule^.^^.^^ This shift of activation site may well represent a way of preventing overreactions to antigen-specific response within the lamina propria, indicating control at the level of the ligand-receptor interaction. The predominant receptors on lamina propria T cells which activate function appear to be CD2. A predominant auxiliary molecule is CD28.37,38 These T cell receptors bind the natural ligands LFA3, and B7/BB-l, re~pectively.~’.~~ LFA3 is present on most cell types and B7/BB-1 on B ~ e l l s . ~Therefore, ~-~l activation of lamina propria T cell functions, and cytokine production and release, depend more on cell to cell interactions than responses to specific antigens. These findings indicate that similar studies are needed to determine the preferential signals that induce cytokine release from other mucosal cells such as fibroblasts, epithelial cells, smooth muscle cells or macrophages. Cytokine “networks” which allow “cross talking” between these vastly different cell populations are extremely important in regulation of immune response as well as controlling the level of inflammation following host perturbation. Furthermore, not only is the repertoire of cytokines that are produced important to determine regulation, but also the responsiveness of the resident cell populations to the presence of these cytokines. This cellular response is controlled by induction and expression of specific receptors on responder cells, as well as induction of potential receptor antagonists. An example of the importance of studying the regional cells for understanding this regulation relates to the inhibition of T cell cytokine production by PGE2. Recent studies have suggested that the rnucosal T cell is 100-1000 times less responsive to inhibition of cytokine production by PGE2. Therefore, the relative refractoriness of T cells to downregulation may create a more permissive environment for chronic inflammation in the lamina propria than
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in other immune compartment^.^^ The responsiveness of other resident cell populations to regulatory cytokines should be studied intrinsically within that compartment.
CONCLUSION The lamina propria of the intestine is the cellular layer which lies between the intraepithelial compartment and the circulation, and is comprised of a great many reactive cell types that can respond differently to challenges from the environment. The compartment is unique not only in the cell types, but also their expression of receptors, activation states, and responsiveness to exogenous signals. The regulation of these cells as responders to the environment is tightly controlled and dynamic repopulation is perpetual. The critical points of regulation are at the level of signal responsiveness, induction of receptors, and responsiveness to receptor ligation. The signalling process that initiates cell migration from the Peyer’s patches, the remigration of these cells to the lamina propria, as well as activation within the lamina propria is extremely complex. This series of activity is under selective investigation and is beginning to be elucidated at the molecular level. Subsequent papers will address the responsiveness of these cell types and their interaction with other resident cell populations within the mucosa. REFERENCES I . TARGAN,S . R., M. F. KAGNOFF,M. D. BROGAN& F. SHANAHAN. 1987. Immunologic mechanisms in intestinal diseases. Ann. Intern. Med. 106: 853-870. 2. STOBER, W. & W. R. BROWN.1988. The mucosal immune system. In Immunological Diseases. Vol. 1. M. Samter, D. W. Talmage, M. M. Frank, K . F. Austen & H. N . Claman, Eds. 70-139. Little, Brown and Co. Boston. 3. BIENENSTOCK, J., M. MCDERMOTT, D. BEFUS& M. O’NEILL.1978. A common mucosal immunologic system involving the bronchus, breast, and bowel. Adv. Exp. Med. Biol. 107: 53. 4. JAMES,S. P. Mucosal immunity. In Basic and Clinical Immunology. L. H. Sigal, R. Yaacor & P. Flood, Eds. McGraw Hill. New York. In press. 5 . DOBBINS, W. 0. 1982. Gut irnmunophysiology: a gastroenterologist’s view with emphasis on pathophysiology. Am. J. Physiol. 242: GI-8. 6. SELL,S., C. RAFFEL& C . B. SCOTT.1980. Tissue localization of T and B lymphocytes in lagomorphs: anatomical evidence for a major role in the gastrointestinal associated lymphoid tissue in generation of lymphocytes in the adult. Dev. Comp. Immunol. 4: 355-366. 7. KAGNOFF,M. F. 1987. Immunology of the digestive system. In Physiology of the gastrointestinal tract. L. R. Johnson, Ed. 1699-1728. Raven Press. New York. 8. BOCKMAN,D. E. & M. D. COOPER.1973. Pinocytosis by epithelium associated with lymphoid follicles in the bursa of Fabricius, appendix and Peyer’s patches: an electron microscopic study. Am. J. Anat. 136: 455-477. 9. WOLF,J. L. & W. A. BYE. 1984. The membranous epithelial (M)cell and the mucosal immune system. Annu. Rev. Med. 35: 95-112. 10. OWEN,R. L. 1977. Sequential uptake of horesradish peroxidase by lymphoid follicle epithelium of Peyer’s patches in the normal unobstructed mouse intestine: an ultrastructural study. Gastroenterology 72: 440-446. 11. OWEN,R. L. & A. L. JONES.1974. Epithelial celi specialization within human Peyer’s patches: an ultrastructural study of intestinal lymphoid follicles. Gastroenterology 66: 189-203.
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12. SCHIEFERDECKER, H. L., R. ULLRICH,A. J. WEISS-BRECKWOLDT, R. SECHWARTING, H. STEIN,E. RIECKEN& M. ZEITZ. 1990. J. Immunol. 144: 2541-2549. M., L. TERRY,R. EDWARDS,P. C. L. BEVERLEY.1988. Eur. J. 13. MERKENSCHLAGER, Immunol. 18: 1653-1658. 14. JAMES,S. P., W. C. KWAN& M. C. SNELLER.1990. T cells in inductive and effector compartment of the intestinal mucosal immune system of nonhuman primates differ in lymphokine mRNA expression, lymphokine utilization and regulatory function. J. Immunol. 1251: 1256. G. FULOP,D. G. HARNISH,L. D. IS. CROITURU,K., R. H. STEAD,J. BIENENSTOCK, SHULTZ,P. K. JEFFERY& P. ERNST. 1990. Presence of intestinal intraepithelial lymphocytes in mice with severe combined immunodeficiency disease. Eur. J. Immunol. 20: 645-651. S. ITOHARA,S. DEGERMANN, C. HEUSSER,S. To16. BANDEIRA,A., T. MOTA-SANTOS, NEGAWA & A. COUTINHO. 1990. Locahzation of gamma/delta T cells to the intestinal epithelium is independent of normal microbial colonization. J. Exp. Med. 172: 239-244. T., W. K. AICHER,J. MEGA,K. FUJIHASHI, K. W. BEAGLEY, J. R. MCGHEE, 17. TAGUCHI, S. OTAKE& H. KIYONO.1990. CD3 + ,CD8 intraepithelial lymphoM. HIRASAWA, cytes produce both IL-5 and IL-6. FASEB J. A2037. 18. EBERT,E. C. 1990. Intra-epithelial lymphocytes: interferon gamma production and suppressorlcytotoxic activities. Clin. Exp. Immunol. 82: 81-85. J. R. MCGHEE,J. H. ELDRIDGE,M. G. BRUCH,D. R. 19. FUJIHASHI,K., T. TAGUCHI, GREEN,B. SINGH& H. KIYONO.1990. Regulatory function for murine intraepithelial lymphocytes. Two subsets of CD3 + , T cell receptor 1 + intraepithelial lymphocyte T cells abrogate oral tolerance. J. Immunol. 145: 2025-2034. K. ZIEGLER,E. 0. RIECKEN& M. ZEITZ.1990. 20. ULLRICH,R., H. L. SHIEFERDECKER, Gamma delta T cells in the human intestine express surface markers of activation and are preferentially located in the epithelium. Cell. Immunol. 12s: 619-627. 21. EBERT,E. C. 1989. Proliferative response of human intraepithelial lymphocytes to various T cell stimuli. Gastroenterology 97: 1372-1381. J., G . RADCLIFFE,YI-C. LIN, J. NIETUPSKI, L. BERGGREN, R. SITIA& 22. STAVNEZER, E. SEVERINSON. 1988. Immunoglobulin heavy-chain switching may be directed by prior induction of transcripts from constant-region genes. Proc. Natl. Acad. Sci. USA 85: 7704-7708. J., S. SIRLIN& J. ABBOT. 1985. Induction of immunoglobulin isotype 23. STAVNEZER, switching in cultured 1.29 B lymphoma cells. Characterization of the accompanying rearrangements of heavy chain genes. J. Exp. Med. 161: 577-601. DA, F. D.LEE& R. L. COFFMAN.1990. Mechanism for transforming growth 24. LEBMAN, factor beta and IL-2 enhancement of IgA expression in lipopolysaccharide-stimulated B cell cultures. J. Immunol. 144: 952-959. 25 KIM,P. H. & M. F. KAGNOFF.1990. Transforminggrowth factor-beta I isacostimulator for Iga production. J. Immunol. 144: 341 1-3416. 26. KIM, P. H. & M. F. KAGNOFF.1990. Transforming growth factor bl increases IgA isotype switching at the clonal level. J. Immunol. 145: 3773-3778. T. A. 1990. Adhesion receptors of the immune system. Nature 346.425-434. 21. SPRINGER, 28. BERG, E. L., L. A. GOLDSTEIN,M. A. JUTILA,M. NAKACHE,L. J. PICKER,P. R. STREETER, N. W. Wu, D. ZHOU& E. C. BUTCHER.1989. Homing receptors and vascular addressins: cell adhesion molecules that direct lymphocyte traffic. Immunol. Rev. 108: 1-18. T. A. YEDNOCK, D.DOWBENKO, C. FENNIE, H. RODRI29. LASKY,L. A., M. S. SINGER, GUEZ,T. NGUYEN,S. SATCHEL & D.ROSEN.1989. Cloning of a lymphocyte homing receptor reveals a lectin domain. Cell 5 6 1045-1055. D. M., R. F. BARGATZE & E. C. BUTCHER.1987. A common endothelial 30. LEWINSOHN, cell recognition system shared by neutrophils, lymphocytes, and other leukocytes. J. Immunol. 138 4313. M., E. L. BERG,P. R. STREETER & E. C. BUTCHER.1989. The mucosal 31. NAKACHE, vascular addressin is a tissue-specific endothelial cell adhesion molecule for circulating lymphocytes. Nature 337: 179-181.
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tL. A. LASKY. 1991. Neutrophil influx into aninflammatory 32. WATSON,S. R., C. FENNIE site inhibited by a soluble homing receptor-lgG chimaera. Nature 349: 164. S., R. F. BARGATZE, J. DE LOSTOYOS & E. C. BUTCHER.1987. Lymphocyte 33. JALKANEN, recognition of high endothelium. J. Cell Biol. 105: 983-990. 34. CHIN,Y-H., J-P. CAI & K. JOHNSON. 1990. Lymphocyte adhesion to cultured Peyer’s patch high endothelial venule cells is mediated by organ-specific homing receptors and can be regulated by cytokines. J. Immunol. 145: 3669-3677. 35. HAMANN,A., D. JABLONSKI-WESTRICH, L-L. SCHOLZ,A. DUIJVESTIJIN,E. C. BUTCHER& H-G. THIEL. 1988. Regulation of lymphocyte homing. I. Alterations in homing receptor expression and organ-specific high endothelial venule binding of lymphocytes upon activation. J. Immunol. 140: 737-743. 36. HARLAN,J. M., N. B. VEDDER,R. K. WINN & C. L. RICE. 1991. Mechanisms and consequences of leukocyte-endothelial interaction. West. J. Med. 155: 365-369. 1991. Role of mucosal T cell generated 37. TARGAN,S., R. DEEM & F. SHANAHAN. cytokines in epithelial cell injury. Immunol. Res. 10: 472-478. 38. TARGAN, S . , R. DEEM& A. NEL. 1991. Importance of the CD2 activation pathway in production of cytotoxic cytokines from lamina propria T cells. Gastroenterology 100: A620. 39. SHAW,S., G. E. G. LUCE,R. QUINONES er al. 1986. Two antigen-independent adhesion pathways used by human cytotoxic T-cell clones. Nature 323: 262. 40. SELVARAJ,P., M. L. PLUNKETT, M. DUSTINeral. 1987. The T lymphocyte glycoprotein C D 2 binds the cell surface ligand LFA-3. Nature 326 400. 41. LINSLEY,P. S., E. A. CLARKL J. A. LEDBETTER. 1990. Proc. Natl. Acad. Sci. USA 87: 5031-5035. 42. DEEM,R. L., A. NEL & S. R. TARGAN. 1992. Relative refractoriness of lamina propria v. peripheral blood T cell cytokine production to down-regulation by prostaglandin E-2. Gastroenterology. In press.
INTRODUCTION The lamina propria is the layer of the intestinal wall which lies between the epithelium and the muscularis mucosae. The lamina propria has unique immune properties, and functions as a component of the mucosal immune system. Therefore, this paper provides a description of the lamina propria within the context of the encompassing mucosal immune system.'q2 The nature and interaction of the many cell types present within the lamina propria are described. This complement of cells undergo a perpetual process of activation, migration and homing to effect an environmental defense. Comprehension of cellular trafficking to this compartment will permit insight into the interaction between lamina propria cells and the resident endothelial cells, fibroblasts, smooth muscle cells and epithelial cells which exquisitely regulate the immune response.
The Mucosal Immune System The mucosal-associated lymphoid tissue (MALT) (FIG.1) represents a unique immune compartment with distinct characteristic^.^ Primary mucosal responses are initiated yet systemic responses are suppressed in the MALT. Due to its proximity to the host's environmental interface, the MALT is the initial line of immune defense for the host's interaction with its environment. This tissue has evolved to balance two opposing environmental pressures. First, the MALT provides protection to the host from invading organisms from the outside environment. Secondly, the MALT induces immune tolerance to numerous harmless environmental antigens so that the immune system does not become overwhelmed and indirectly injure the host. The balance between these two potentially conflicting responses is maintained by a system of exquisite regulat i ~ n . ' - * The * ~ lamina propria is located subepithelially within the intestinal wall. Typically, 'inflammatory cells' exist within the mucosa; therefore, an inflammatory infiltrate is normally present in the lamina propria. Cells within the lamina propria appear to migrate from other areas or are generated locally, and both can be induced to differentiate by local environmental factors. The functioning mucosal structure can be divided into afferent and efferent limbs (FIG. 2).5-7 Within the afferent limb are the specialized areas of the intestine in which lymphocytes of both B and T cell phenotypes as well as 61
62
ANNALS NEW YORK ACADEMY OF SCIENCES
FIGURE 1. Diagram of the common mucosal-associated lymphoid tissues (MALT). Shows dissemination of effector cells from an intestinally-generated immune response throughout the entire MALT. (Reprinted by permission from the Journal of Allergy and Clinical Immunology.)
macrophages are aggregated; referred to as lymphoid aggregates, or Peyer's patches. A specialized intestinal epithelium (comprised of membranous M cells) stretches over the domes of these lymphoid aggregates.*-" These cells are capable of sampling antigens from the intestinal environment; both viable particulate antigens as well as soluble antigens are bound to these cells.9 In addition to local lymphoid follicles, there are differences in the lamina propria cell types within different regions of the gastrointestinal tract. In the colon and in the ileum, there appears to be an increased number of organized lymphoid follicles compared to the more proximal intestine.2 Physiologically this may be so that antigen sampling of the environment may occur in areas where absorbed antigens have been removed. There are two distinct compartments within the efferent limb of the mucosa: the lamina propria and the intraepithelial compartment (see FIG. 2). The nonorganized, efferent area of the lamina propria (FIG.2) consists of multiple cell types, capable of inflammatory responses (many of which will be discussed in detail in subsequent papers). These include T and B lymphocytes, macrophages, neutrophils, eosinophils, mast cells, endothelial cells, tissue fibroblasts, smooth muscle cells, and epithelial cells. The proximity of these cells to each other provides for multiple potential interactions among cell types. The fact that most T cells within the lamina propria are activated and are of the memory phenotype12v13 make this compartment one in which there are higher levels of inducible
TARGAN LAMINA PROPRIA
63
cytokines as compared to other immune compartments. l4 Overlying these cells within the epithelium are the intraepithelial lymphocytes. The intraepithelial compartment consists mainly of unique T cells with very few, if any B cell^.^^-*^ The nature of the T cell receptors on these cells varies depending upon the species. In rodents the majority of the intraepithelial T cells express T-yi3.I6 In humans, the vast majority of the T cells are T-aP.*O Most of these are of the CD8+ phenotype. The cells are cytotoxic and can release c y t ~ k i n e s . ' ~ The -'~ intraepithelial lymphocytes respond to signals through different receptors than systemic T cells in that they do not respond through the T cell receptor but can be activated through the CD2 accessory pathway.*' Recently, it has been suggested that these cells could become autoreactive, particularly responding to non-MHC antigens expressed on epithelial cells (Kronenberg M, personal communication). The dynamic structure of the lamina propria, as well as intraepithelial lymphocyte compartment is unique, in that there are large numbers of inflammatory cells which have the potential to not only protect the host but also injure it, Therefore, tight regulation of these agents of destruction is critical for host survival.
AFFERENT
EFFERENT
ANTIGEN
THORACIC DUCT
FIGURE 2. Schematic representation of the structure and movement of the afferent and efferent circuits of the mucosal immune compartment. IEL = intraepithelial lymphocyte; MLN = mesenteric lymph node. (Reprinted by permission from the Annals oflnternal Medicine.)
64
ANNALS NEW YORK ACADEMY OF SCIENCES
Lamina Propria: Important Control Points Traficking
Vital to understanding of the lamina propria as an immune compartment is definition of the mechanisms that regulate its dynamic characteristics. FIGURE 3 depicts the cellular trafficking patterns following a response to an environmental antigen. The antigen is expressed by specialized cells (Mcells) within the epithelium that overlay Peyer’s patches.I4 The antigen is transported into the mucosa where macrophages pinocytose, process and re-express the antigen on their cell
FIGURE 3. Repertoire of cells and soluble mediators in the lamina propria primed for inflammatory responses.
surfaces in association with major histocompatibility complex molecules. This aggregate then induces both T and B cell responses by triggering cell activation and selected cytokine release (ILl, TGFB, IL6, IL5) within the Peyer’s patches. These cytokines participate in altering the production by mucosal B cells of immunoglobulin to the IgA isotype that predominates in the intestinal secretions within the mucosa.22-26 Following activation and differentiation, T and/or B cells migrate from the Peyer’s patch. The signalling process that induces migration, however, remains to be defined. The cells migrate to the mesenteric lymph nodes where further activation and production of responsive clones occurs. The blast cells then traffic through the thoracic duct back into the circulation and by specific ligand-
65
TARGAN: LAMINA PROPRIA
ligand interaction^^'-^^ bind to and then cross the endothelium, thereby homing specifically to the lamina p r ~ p r i a . ~ ~ The regulation of cell surface glycoproteins and receptors in both circulating effector cells and endothelial cells plays the key role determining the trafficking of lymphocytes and neutrophils into the lamina p r ~ p r i a . ’ ~It. ~appears ~ as though expression of glycoproteins and receptors is induced by inflammatory cytokines and therefore trafficking patterns of cells to the lamina propria can be altered by providing chemotactic signals as well as by enhancing expression of ligands and receptor^.^^.^* Arachidonic acid products and T cell- and fibroblast-associated cytokines such as IL-8 which induce expression of ELAMs, ICAMs, or VLAMs on endothelial cells are chemotactic for n e ~ t r o p h i l sOnce . ~ ~ circulating cells are bound by these ligands, other ligand interactions promote movement through the endothelium within the lamina p r ~ p r i a . ~ ’ , ~The ~ , ~phenomenon ’ of CD8 T cell migration from the lamina propria into the intraepithelium is not clearly understood. This homing process allows a wide dissemination of an isolated response to exogenous antigen. For example, a response generated in the ileum may send specific antigen responsive cells to the rest of the small intestine, the colon, lung and salivary glands. What determines the extent of dissemination also remains undefined.
+
Signals
The lamina propria cells respond to different signals than the cells from other immune compartments. For example, in the systemic immune system T cell responses are preferentially driven through the T cell receptor. In contrast, the lamina propria T cell responds best when signalling occurs via alternate pathways and auxiliary molecule^.^^.^^ This shift of activation site may well represent a way of preventing overreactions to antigen-specific response within the lamina propria, indicating control at the level of the ligand-receptor interaction. The predominant receptors on lamina propria T cells which activate function appear to be CD2. A predominant auxiliary molecule is CD28.37,38 These T cell receptors bind the natural ligands LFA3, and B7/BB-l, re~pectively.~’.~~ LFA3 is present on most cell types and B7/BB-1 on B ~ e l l s . ~Therefore, ~-~l activation of lamina propria T cell functions, and cytokine production and release, depend more on cell to cell interactions than responses to specific antigens. These findings indicate that similar studies are needed to determine the preferential signals that induce cytokine release from other mucosal cells such as fibroblasts, epithelial cells, smooth muscle cells or macrophages. Cytokine “networks” which allow “cross talking” between these vastly different cell populations are extremely important in regulation of immune response as well as controlling the level of inflammation following host perturbation. Furthermore, not only is the repertoire of cytokines that are produced important to determine regulation, but also the responsiveness of the resident cell populations to the presence of these cytokines. This cellular response is controlled by induction and expression of specific receptors on responder cells, as well as induction of potential receptor antagonists. An example of the importance of studying the regional cells for understanding this regulation relates to the inhibition of T cell cytokine production by PGE2. Recent studies have suggested that the rnucosal T cell is 100-1000 times less responsive to inhibition of cytokine production by PGE2. Therefore, the relative refractoriness of T cells to downregulation may create a more permissive environment for chronic inflammation in the lamina propria than
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ANNALS NEW YORK ACADEMY OF SCIENCES
in other immune compartment^.^^ The responsiveness of other resident cell populations to regulatory cytokines should be studied intrinsically within that compartment.
CONCLUSION The lamina propria of the intestine is the cellular layer which lies between the intraepithelial compartment and the circulation, and is comprised of a great many reactive cell types that can respond differently to challenges from the environment. The compartment is unique not only in the cell types, but also their expression of receptors, activation states, and responsiveness to exogenous signals. The regulation of these cells as responders to the environment is tightly controlled and dynamic repopulation is perpetual. The critical points of regulation are at the level of signal responsiveness, induction of receptors, and responsiveness to receptor ligation. The signalling process that initiates cell migration from the Peyer’s patches, the remigration of these cells to the lamina propria, as well as activation within the lamina propria is extremely complex. This series of activity is under selective investigation and is beginning to be elucidated at the molecular level. Subsequent papers will address the responsiveness of these cell types and their interaction with other resident cell populations within the mucosa. REFERENCES I . TARGAN,S . R., M. F. KAGNOFF,M. D. BROGAN& F. SHANAHAN. 1987. Immunologic mechanisms in intestinal diseases. Ann. Intern. Med. 106: 853-870. 2. STOBER, W. & W. R. BROWN.1988. The mucosal immune system. In Immunological Diseases. Vol. 1. M. Samter, D. W. Talmage, M. M. Frank, K . F. Austen & H. N . Claman, Eds. 70-139. Little, Brown and Co. Boston. 3. BIENENSTOCK, J., M. MCDERMOTT, D. BEFUS& M. O’NEILL.1978. A common mucosal immunologic system involving the bronchus, breast, and bowel. Adv. Exp. Med. Biol. 107: 53. 4. JAMES,S. P. Mucosal immunity. In Basic and Clinical Immunology. L. H. Sigal, R. Yaacor & P. Flood, Eds. McGraw Hill. New York. In press. 5 . DOBBINS, W. 0. 1982. Gut irnmunophysiology: a gastroenterologist’s view with emphasis on pathophysiology. Am. J. Physiol. 242: GI-8. 6. SELL,S., C. RAFFEL& C . B. SCOTT.1980. Tissue localization of T and B lymphocytes in lagomorphs: anatomical evidence for a major role in the gastrointestinal associated lymphoid tissue in generation of lymphocytes in the adult. Dev. Comp. Immunol. 4: 355-366. 7. KAGNOFF,M. F. 1987. Immunology of the digestive system. In Physiology of the gastrointestinal tract. L. R. Johnson, Ed. 1699-1728. Raven Press. New York. 8. BOCKMAN,D. E. & M. D. COOPER.1973. Pinocytosis by epithelium associated with lymphoid follicles in the bursa of Fabricius, appendix and Peyer’s patches: an electron microscopic study. Am. J. Anat. 136: 455-477. 9. WOLF,J. L. & W. A. BYE. 1984. The membranous epithelial (M)cell and the mucosal immune system. Annu. Rev. Med. 35: 95-112. 10. OWEN,R. L. 1977. Sequential uptake of horesradish peroxidase by lymphoid follicle epithelium of Peyer’s patches in the normal unobstructed mouse intestine: an ultrastructural study. Gastroenterology 72: 440-446. 11. OWEN,R. L. & A. L. JONES.1974. Epithelial celi specialization within human Peyer’s patches: an ultrastructural study of intestinal lymphoid follicles. Gastroenterology 66: 189-203.
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