The fundamental purpose of the immune system is to distinguish between self and non-self. Foreign antigens
Handbook of Models for Human Aging
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are eliminated in a variety of ways by both the so-called innate and adaptive components of the immune system. The innate immune system deals with foreign invaders through rapid, albeit fairly nonspecific, responses. Moreover, there is no recall or memory within the innate immune system. By contrast, the adaptive immune system takes a bit longer to respond, but retains memory for the specific antigen, and is able to respond in an accelerated fashion in the event of re-encounter with the same antigen. Indeed, it is this ability to ''learn'' and remember specific antigens that is the basis for vaccination.
The two major types of lymphocytes that comprise the adaptive immune system are B cells and T cells. Both are derived from hematopoetic stem cells in the bone marrow, but they function in entirely different ways. B cells produce soluble proteins known as antibodies, which can neutralize or otherwise inhibit the activity of foreign pathogens. Thus, B cells are responsible for the so-called humoral immune response. T cells, on the other hand, cannot recognize anything foreign unless it has actually entered another cell. The infected cell, which expresses parts of the virus or bacterium on its surface, is recognized as non-self by the T cells, eliciting what is known as ''cellular immunity.''
How do B cells and T cells recognize foreign pathogens that enter the body? The recognition structures, known as antigen receptors, are generated through a unique and complex set of genetic events, which allows a limited number of genes to create an immune system with an enormous range of specificities. Briefly, during the development of lymphocytes, one member of a set of gene segments is randomly joined to other gene segments by an irreversible process of DNA recombination. The consequence of this mechanism is that just a few hundred different gene segments can combine in a variety of ways to create thousands of receptor chains. This diversity is further amplified by the pairing of two different chains, each encoded by distinct sets of gene segments, to form a functional antigen receptor. Each lymphocyte bears many copies of its antigen receptor, and once generated, the receptor specificity of a lymphocyte does not change. Thus, only one specificity can be expressed by a single lymphocyte and its progeny (Janeway Jr et al., 2001).
CLONAL EXPANSION—WHAT ABOUT THE HAYFLICK LIMIT?
Because of the random nature of the genetic events that create lymphocyte receptors, a small amount of genetic material is utilized to generate at least 108 different specificities. The corollary to this is that since each lymphocyte bears a different antigen receptor, the number of lymphocytes that can recognize any single foreign antigen is exceedingly small. Therefore, when a mature lymphocyte interacts with a particular antigen that is recognized by its receptor, that lymphocyte becomes activated and must begin dividing, giving rise to a clone of identical progeny bearing identical receptors for antigen. Antigen specificity is thereby maintained as the dividing cells continue to proliferate and differentiate into effector cells. Once antigen is cleared, a small number of memory cells persist, all bearing the same antigen receptor. When the same antigen is encountered again, the process of activation and clonal expansion is repeated (Janeway Jr et al., 2001).
From what has been described above, it becomes clear that cell proliferation is a central feature of adaptive immunity. One wonders, then, how the so-called Hayflick Limit might affect the behavior of cells within the immune system. This innate barrier to unlimited cell division, known as replicative senescence, has been documented for a variety of cell types, and would seem to be highly relevant to T cells, whose ability to fight infections is critically dependent on extensive cell division.
From the cell culture data on other cell types, a preliminary estimate would suggest that the degree of proliferation achievable by each T cell is so large that the finite replicative lifespan would not necessarily be biologically meaningful in vivo. For example, if a T cell has an average proliferative lifespan of 35 population doublings, and even if all daughter cells continue to grow unchecked, the resulting yield of more than 1010 cells would appear to be more than sufficient. However, because T-cell immune responses include both extensive proliferation and apoptotic removal of excess cells, the finite proliferative lifespan of T cells might allow only two or three rounds of antigen-driven expansion before the end stage of replicative senescence is reached. The above crude estimate suggests that the limited prolifera-tive potential might indeed be detrimental in vivo, particularly by old age (Effros and Pawelec, 1997).
Based on the importance of cell proliferation in maintaining effective immune function, we sought to examine the changes that T cells undergo as they progressed through their proliferative lifespan. In order to ensure that we were studying the same population of T cells over time, the most suitable method to address this issue is in cell culture, where it is possible to conduct a virtual longitudinal study on a specific set of cells. Long-term cell culture analyses had been performed on other cell types, including fibroblasts, epithelial cells, endo-thelial cells and keratinocytes, to characterize the unique features of each cell type under conditions of enforced, extensive prolilferation (Campisi, 1997). Ironically, until fairly recently, T cells, whose function is critically dependent on clonal expansion, had never been examined with respect to the process of replicative senescence (Adibzadeh et al., 1995; Effros, 1996). In the following section, we describe our adaptation of the long-term culture techniques to human T cells, and summarize the main features of replicative senescence in this cell type.
Primary Cultures of Human T Cells
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