Opinion VIEWPOINT Discovery of 2 Distinctive Lineages of Lymphocytes, T Cells and B Cells, as the Basis of the Adaptive Immune System and Immunologic Function 2019 Albert Lasker Basic Medical Research Award Max Dale Cooper, MD The 2019 Albert Lasker Basic Medical Research Award has such as wasting, thought to be the result of infection by Emory University been presented to Max Dale Cooper and Jacques F.A. P.Miller organisms present in the environment, notably mouse School of Medicine, for discovery of the 2 distinct classes of lymphocytes, B and hepatitis virus. They showed a marked deficiency of lym- Atlanta, Georgia. T cells, a monumental achievement that provided the orga- phocytes both in the circulation and lymphoid tissues. nizing principle of the adaptive immune system and launched Their antibody responses to certain antigens were di- Jacques F. A. P.Miller, the course of modern immunology. MD, PhD minished; skin grafts from foreign strains of mice, and The Walter and Eliza even from rats, were not rejected.1,2 Germ-free mice Hall Institute of Medical To survive and resist invasion by pathogens, all living raised in a sterile environment did not develop any signs Research, Parkville, organisms have evolved mechanisms of defense. of ill health after neonatal thymectomy but still showed Victoria, Australia. In a general way, a distinction can be made between defects in immune responsiveness. constitutive mechanisms, which do not depend on the Lethally irradiated mice that were thymectomized introduction of something new into the body to as adults can be rescued by injection of bone marrow Viewpoint induce their development, and adaptive mechanisms, cells but are still immunodeficient. Even nonlethal pages 1249 and 1251 which require the entry of some foreign agent or anti- whole-body irradiation can destroy lymphocytes along gen to stimulate their formation. In both vertebrates with members of rapidly dividing hematopoietic and and invertebrates, constitutive mechanisms are non- epithelial populations of cells, and this explains why specific and often associated with cells that perform mice that were thymectomized as adults and subse- the function of phagocytosis. Adaptive mechanisms quently irradiated became as immunoincompetent as are specific and exemplified by acquired immunity, mice that were neonatally thymectomized.3 The eluci- which is a function of lymphocytes. Although these dation of these irradiation effects would also lead to cells circulate in blood and lymph, they are concen- the design of experimental models that allowed dissec- trated in lymphoid organs, such as the thymus, bone tion of the immunological roles of different cell types. marrow, spleen, and lymph nodes, and gut-associated Implanting thymus tissue in neonatally thymecto- structures, such as the tonsils, adenoids, Peyer’s mized mice enabled them to perform immune func- patches, and appendix. tions as efficiently as normal mice.2 When the thymus The thymus differs from other lymphoid organs graft was taken from a foreign strain, the thymecto- both structurally and functionally. It is relatively large in mized recipients were specifically immunologically tol- infants, reaches its maximum size of about 40 g around erantofthehistocompatibilityantigensofthedonor,sug- 3 years of age, and then gradually regresses to become gesting that self-tolerance is, at least in part, a function little more than a vestigial structure in old age. For cen- of the thymus.2 turies, it had remained an enigmatic organ, and conten- When placed in culture, an epithelial thymus from tions and controversies abounded regarding its embry- a mouse embryo becomes filled with lymphocytes ology, anatomy, physiology, pathology, and clinical over the next few days. Related studies in mature significance. As late as 1960, immunologists did not mice showed that circulating lymphocytes labeled consider that the thymus or its lymphocytes had any with a DNA marker often leave the bloodstream to significant role in immunity for several reasons. First, enter lymphoid tissues, like the spleen and lymph the cytological hallmarks of an immune response, such nodes, before subsequently migrating via lymphatic as plasma cell development and germinal center forma- channels to reenter the circulation. Some of the tion, were never seen in the thymus of normal immu- labeled small lymphocytes were noted to become nized animals. Second, thymus lymphocytes, unlike plasma cells. These findings suggested that thymus- cells from other lymphoid tissues, could not initiate or derived lymphocytes circulate throughout the body transfer an immune response to antigen in appropriate and can respond to stimulation in peripheral lymphoid Corresponding recipients. Third, animals thymectomized in adult life tissues to differentiate into the plasma cells that pro- Author: Max Dale Cooper, MD, produced both antibody-independent “cellular” duce antibodies. Emory University immune responses and antibody-dependent “humoral” This idea of a single lymphocyte lineage was chal- School of Medicine, immune responses as efficiently as intact animals. lenged, however, by observations in other vertebrate 1462 Clifton Rd, In contrast to mice that were thymectomized in species. One important discovery, which was made DSB 403C, Atlanta, GA 30322 (mdcoope@ adult life, mice that were neonatally thymectomized de- by poultry scientists in 1956, went unnoticed by most emory.edu). veloped, some weeks after weaning, signs of ill health, contemporary immunologists. In addition to having jama.com (Reprinted) JAMA October 1, 2019 Volume 322, Number 13 1247 © 2019 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Opinion Viewpoint a thymus, birds have a lymphoid organ called the bursa of Fabricius, irradiatedbursalymphocytesrestoredgerminalcenters,plasmacells, sometimes nicknamed the “cloacal thymus” because of its location and immunoglobulin production.6 above the cloaca and its histological appearance. A postulated These results were indicative of 2 distinctive lineages of lym- endocrine role of the bursa was not supported by the normal phocytes, a thymus-dependent lineage of lymphocytes that was growth and sexual development of chicks following early bursec- primarily responsible for cellular immunity and a bursa-dependent tomy, but severe impairment of antibody responses was fortu- lineage of cells that was responsible for antibody production and itously discovered in these bursa-less birds. Testosterone treat- humoral immunity. Contemporaneous studies defining hematopoi- ment of chick embryos also inhibited bursa development and etic stem cells suggested these could be the precursors of both antibody production, and this “chemical bursectomy” sometimes lymphocyte lineages. Validation of this compartmentalized model impaired thymus development as well. Subsequent studies sug- of lymphocyte development in humans was provided by the gested the avian thymus and bursa could differentially influence plasma cell development and antibody production observed in cellular and humoral immune functions, but the functional effects congenitally athymic patients. of early thymectomy were inconsistent in different chicken strains Experiments in which the techniques of thymectomy, irradia- and difficult to correlate with related studies in mammals. tion, and inoculation of genetically marked cells from the lymph and Patients with familial immunodeficiency diseases offered ad- from bone marrow were combined indicated that thymus-derived ditional insight into immune system development. Boys who had re- cells (now called T cells) were not antibody-producing cells, but current bacterial infections because of congenital agammaglobu- helped other lymphocytes derived from bone marrow (now called linemia were noted to be deficient in germinal centers and plasma B cells) to produce antibody.7 Collectively, these findings estab- cells, although their thymus and lymphocyte levels were normal, and lished that the adaptive immune system is based on 2 universes of they could control most virus infections. Conversely, boys with lymphocytes, one T-celldependent and responsible for cellular im- Wiskott-Aldrich syndrome (frequent ear infections, eczema, and munity,as in graft rejection and in the control of virus infections, the platelet deficiency) were found to have an atrophic thymus, severe other B-cell dependent and involved in humoral immunity by means lymphocyte deficiency, and inability to survive herpes simplex vi- of antibody secretion. rus infection, despite having an abundance of plasma cells and their A search for the origin of adaptive immunity has shown that immunoglobulin products. the basic genetic program for the T and B lineages of lymphocytes These findings, which were not consistent with the single lym- is conserved in both jawed and jawless vertebrates and thus phocyte lineage model, led to a revisit of the avian model, but this already existed in a common vertebrate ancestor approximately time with near-lethal whole-body irradiation in addition to thymus 500 million years ago.8 For antigen recognition, however, lympho- or bursa removal at hatching in order to destroy immune cells that cytes in the jawless vertebrates (lampreys and hagfish) use highly might have developed earlier. When the birds that had been thy- variable lymphocyte receptors encoded by leucine-rich-repeat mectomized and irradiated were examined after recovery from ir- gene segments instead of immunoglobulin gene segments.