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The role of T lymphocytes in inflammation.

Lymphocytes, together with monocytederived macrophages, are common participants in inflammatory responses associated with various forms of tissue injury, ranging from normal wound repair to the inflammatory-fibroproliferative response associated with the advanced lesions of atherosclerosis. Until relatively recently, the association of both CD4+ and CD8+ T lymphocytes with these various inflammatory-fbroproliferative responses, although noted by numerous investigators, has remained poorly understood (1-4). In some instances, it has been assumed that the presence of T lymphocytes signifies some form of immune response in association with the tissue injury. Thus, T cells may enter the lesion in response to plaque neoantigens against which the individual has not yet acquired tolerance (4). On the other hand, it has been suggested that their presence may simply reflect a nonspecific association. Unlike monocyte-derived macrophages, the principal function of T lymphocytes has not been considered to be phagocytic or secretory, but rather to be to produce limited numbers of secreted molecules, and primarily to be involved in cell-cell interactions. Substances such as y-interferon and, more recently, several cytokines have been thought to represent the limited repertoire of molecules potentially formed by T cells. In the report by Blotnick et al. (5), appearing in this issue, convincing evidence is presented to demonstrate that T cells produce two relatively potent growthregulatory molecules-namely, some form of heparin-binding epidermal growth factor-like growth factor (HBEGF), an apparently secreted form of basic fibroblast growth factor (FGF), a molecule which does not normally have a signal sequence and, thus, is not thought to be secreted by the classical secretory pathway. Although it is not clear that the form of basic FGF released by the T lymphocytes demonstrated in this study is similar to several ofthe known forms of FGF that do have signal peptides, the secretion of two such potent growth factors adds a new dimension to the potential role of T lymphocytes not only as components ofthe immune inflammatory response but also as, perhaps equally important, antecedents of the fibroproliferative response associated with inflammation. The production of growthregulatory molecules and cytokines by T cells clearly affords opportunities for T cell-nonimmune cell interactions. In the case of atherosclerosis, both CD4+ and CD8+ T lymphocytes have been shown to be common components of all phases of the lesions present, not only in experimental animals, such as nonhuman primates, but in human lesions in every stage of development (1, 4). Unlike the lesions of atherosclerosis associated with graft rejection after heart transplant, which are symmetrical and contain extraordinarily large numbers of both types of T lymphocytes as well as monocyte-derived macrophages (much greater than those found in the lesions of common atherosclerosis), the presence of CD4+ and CD8+ cells and their possible secretory products in the lesions of common atherosclerosis raises new possibilities to be considered regarding the role of T lymphocytes in the process of atherogenesis. The question ofthe potential antigens that may be responsible for T lymphocyte-macrophage interactions still remains unanswered. However, the role of the lymphocyte, not only in terms of its potential interactions with monocyte-derived macrophages within these inflammatory responses, but in numerous other potentially important disease processes, must now be raised in relation to the possibility that T lymphocytes affect the fibroproliferative response in ways that had not previously been considered. The identification of the two growthregulatory molecules reported by Blotnick et al. (5) represents a somewhat surprising observation. HB-EGF is an extremely potent mitogen for cells that contain EGF receptors and, in particular, for smooth muscle cells potentially involved in the process of atherogenesis. HB-EGF can be secreted by activated monocyte-derived macrophages (6) and by smooth muscle cells (7, 8) but has not heretofore been reported to be secreted by T cells. What factors in vivo could be responsible for the expression ofthe HBEGF gene in these cells? Is the gene expressed in vivo during atherogenesis? Does antigen recognition by appropriate T cells induce expression of the gene? These and other questions raise intriguing possibilities concerning both the role ofT cells in atherogenesis and the importance of this growth factor in this process. As to basic FGF, the evidence suggesting that this molecule is secreted by T cells is equally surprising, unless a modified secretory form of the molecule is expressed by the T cells. The data for both growth factors are intriguing and cast the T cells in a potentially new role, raising questions concerning T cellmacrophage and T cell-smooth muscle interactions in atherogenesis. Thus, the report by Blotnick et al. (5) stimulates one to reconsider the role of the T lymphocyte as a secretory cell in wound healing and in the inflammatoryfibroproliferative responses associated with injury to tissues, such as in liver cirrhosis, in rheumatoid arthritis, and in atherogenesis (9). It remains to be demonstrated whether T lymphocytes actually express the genes for these growth factors in the various disease processes in vivo and whether or not the protein is actually synthesized and secreted in vivo by these cells.