A Developing Story

Lymphocyte Development: Cell Selection Events and Signals during Immune Ontogeny By Shiv Pillai Boston: Birkhauser (2000). 528 pp. $125.00It has been said that students can be classified into one of two major categories. The first is particularly interested in the known and attracted to fields that are relatively well understood. A second category enjoys the challenge of the unknown, choosing areas that are ripe for investigation. Lymphocyte development continues to appeal to the latter. Although extraordinary progress has been made in dissecting components of the immune system and the molecules required for its development, some of the most important issues remain intractable because of the complexity of whole animal systems. Indeed, the field itself is difficult to classify, combining clinical immunology with basic research in hematology, immunology, and developmental biology. Shiv Pillai's new book represents a heroic attempt to ensnare Lymphocyte Development. It is fortunate for the experimentalist that the book is replete with words like “may,” “might,” and “could.”The scope of this book is ambitious, ranging beyond lymphocyte development to recognition, activation, and death. Pillai catalogs the many players in signal transduction biochemistry, reviewing how this increasingly complex set of proteins cooperate to elicit immune system development and function. Although there are recurring themes and helpful diagrams, this will be daunting for newcomers. In addition, technical innovations and clever experimental designs responsible for this massive amount of information could have been given more emphasis.There is intense current interest in learning what endows stem cells of various kinds with extensive self-renewal potential. Pillai discusses multipotential hematopoietic stem cells, and calls to mind an important fact about mature memory lymphocytes. These cells acquire stem cell properties, persist for many years, and expand tremendously when restimulated by antigens. However, they are derived from the differentiation of a series of short-lived precursors and the subsequent activation of short-lived lymphocytes during immune responses. Thus, stem cells of one kind eventually give rise to a different class of specialized stem cells, and we need to know how this nifty trick is accomplished. Knowledge of the mechanisms that control lymphocyte survival and expansion may have implications for understanding many types of stem cells.Transcription factors are key in controlling all aspects of lymphopoiesis and all of them will soon be known. One might assume that the gene targeting approaches so extensively discussed in Pillai's book will easily reveal the hierarchy through which individual transcription factors control the expression, silencing, and actions of other transcription factors involved in immune system development. However, we are far from understanding the precise sequence of differentiation events in those terms and how intracellular gene expression profiles are dictated by extracellular cues.In principle one can explore such issues by determining what genes are expressed in the lymphocytes that remain in immunodeficient knockout animals. However, blood cell production involves enormous expansion so that the closer one gets to stem cells, the fewer there are to study. For that reason, it is often difficult to know if a given gene is silent in a knockout cell or alternatively, if the cell that normally expresses it is missing. High-speed cell sorting and other technical improvements are now making it possible to resolve and isolate extremely rare populations of lympho-hematopoietic cells before study in culture. Because of these advances, many other issues are now accessible to experimentation. For example, we will soon know more precisely when the various blood cell lineages diverge. This should provide insight into a question that has been argued for 40 years about the binary decisions that dividing cells must make. A given cell can renew itself or give rise to daughters with different fates, and the issue is the degree to which the choice is governed by intrinsic versus extrinsic cues. Both probably contribute, but we have much to learn about the selective pressures that ensure that correct numbers of all the types of lymphocytes are produced.There is a growing appreciation of differences in how lymphocytes develop during fetal and adult life. The earliest wave of precursors that emerge in the yolk sac and aorta-gonad-mesonephros (AGM) regions of embryos does not include long-term repopulating stem cells. Stem cells and committed progenitors that emerge later are different in many ways from those in adult marrow. For example, none of the lymphocyte precursors in fetal liver have been shown to fall into the “common lymphoid progenitor” category described in bone marrow. As clearly noted in this book, some gene targeting experiments have differential influences on embryonic and adult lymphopoiesis. It will be interesting to know if and how adult stem cells can be reprogrammed to have fetal characteristics and vice versa.Pillai could have given more stress to differences between humans and experimental animals. For example, interleukin 7 plays essential roles in the production of murine B lineage lymphocytes, supporting the survival, proliferation, and differentiation of lymphocyte precursors. Unfortunately, the cytokine appears not to influence B lymphopoiesis in humans and no factor with comparable function has been found. There are also dramatic species differences in expression of the enzyme TdT during human, but not murine fetal life. This has important consequences for the diversity of lymphocyte antigen receptors at birth, and we should be reminded that our experimental models have limitations.One of the attractive aspects of immunology is the fact that strongly held opinions are frequently demolished by new data. While this is a good thing for the experimentalist, it creates a challenge for textbook authors. Schemes for early stages of lymphocyte differentiation shown in this book are already being questioned and other “likely” scenarios will fall with further study. Fortunately, tables from the book will be available and frequently updated on a web site. It would have been even better if this terrific idea were extended to many of the 156 figures in this volume.Throughout the text, the author treats us to many amusing metaphors. For example, we learn about lymphocyte precursors that are not “truly committed in an irreversible Calvinistic sense.” Immature self-reactive B cells are “given an opportunity to reform themselves” via receptor editing “and become useful citizens.” In contrast to apoptotic cells, “necrotic cells erupt in explosive incandescence, singeing their neighbors and generally trashing the neighborhood.” This lightens the mood and reminds us that lymphocytes are more than lists of molecules.In summary, Pillai casts a wide net—generating a very dense textbook of immunology. Not intended for beginning students, it is nevertheless a very useful reference with nice capsule summaries of such diverse topics as apoptosis, immunodeficiency, and NK cells. While comprehensive, we are left with the certainty that there is much yet to learn about lymphocyte development. That is good news for students looking for a hot field.