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September 10, 2019

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

Author Affiliations
  • 1Emory University School of Medicine, Atlanta, Georgia
  • 2The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
JAMA. Published online September 10, 2019. doi:10.1001/jama.2019.13815

The 2019 Albert Lasker Basic Medical Research Award has been presented to Max Dale Cooper and Jacques F. A. P. Miller for discovery of the 2 distinct classes of lymphocytes, B and T cells, a monumental achievement that provided the organizing principle of the adaptive immune system and launched the course of modern immunology.

To survive and resist invasion by pathogens, all living organisms have evolved mechanisms of defense. In a general way, a distinction can be made between constitutive mechanisms, which do not depend on the introduction of something new into the body to induce their development, and adaptive mechanisms, which require the entry of some foreign agent or antigen to stimulate their formation. In both vertebrates and invertebrates, constitutive mechanisms are nonspecific and often associated with cells that perform the function of phagocytosis. Adaptive mechanisms are specific and exemplified by acquired immunity, which is a function of lymphocytes. Although these cells circulate in blood and lymph, they are concentrated in lymphoid organs, such as the thymus, bone marrow, spleen, and lymph nodes, and gut-associated structures, such as the tonsils, adenoids, Peyer’s patches, and appendix.

The thymus differs from other lymphoid organs both structurally and functionally. It is relatively large in infants, reaches its maximum size of about 40 g around 3 years of age, and then gradually regresses to become little more than a vestigial structure in old age. For centuries, it had remained an enigmatic organ, and contentions and controversies abounded regarding its embryology, anatomy, physiology, pathology, and clinical significance. As late as 1960, immunologists did not consider that the thymus or its lymphocytes had any significant role in immunity for several reasons. First, the cytological hallmarks of an immune response, such as plasma cell development and germinal center formation, were never seen in the thymus of normal immunized animals. Second, thymus lymphocytes, unlike cells from other lymphoid tissues, could not initiate or transfer an immune response to antigen in appropriate recipients. Third, animals thymectomized in adult life produced both antibody-independent “cellular” immune responses and antibody-dependent “humoral” immune responses as efficiently as intact animals.

In contrast to mice that were thymectomized in adult life, mice that were neonatally thymectomized developed, some weeks after weaning, signs of ill health, such as wasting, thought to be the result of infection by organisms present in the environment, notably mouse hepatitis virus. They showed a marked deficiency of lymphocytes both in the circulation and lymphoid tissues. Their antibody responses to certain antigens were diminished; skin grafts from foreign strains of mice, and even from rats, were not rejected.1,2 Germ-free mice raised in a sterile environment did not develop any signs of ill health after neonatal thymectomy but still showed defects in immune responsiveness.

Lethally irradiated mice that were thymectomized as adults can be rescued by injection of bone marrow cells but are still immunodeficient. Even nonlethal whole-body irradiation can destroy lymphocytes along with members of rapidly dividing hematopoietic and epithelial populations of cells, and this explains why mice that were thymectomized as adults and subsequently irradiated became as immunoincompetent as mice that were neonatally thymectomized.3 The elucidation of these irradiation effects would also lead to the design of experimental models that allowed dissection of the immunological roles of different cell types.

Implanting thymus tissue in neonatally thymectomized mice enabled them to perform immune functions as efficiently as normal mice.2 When the thymus graft was taken from a foreign strain, the thymectomized recipients were specifically immunologically tolerant of the histocompatibility antigens of the donor, suggesting that self-tolerance is, at least in part, a function of the thymus.2

When placed in culture, an epithelial thymus from a mouse embryo becomes filled with lymphocytes over the next few days. Related studies in mature mice showed that circulating lymphocytes labeled with a DNA marker often leave the bloodstream to enter lymphoid tissues, like the spleen and lymph nodes, before subsequently migrating via lymphatic channels to reenter the circulation. Some of the labeled small lymphocytes were noted to become plasma cells. These findings suggested that thymus-derived lymphocytes circulate throughout the body and can respond to stimulation in peripheral lymphoid tissues to differentiate into the plasma cells that produce antibodies.

This idea of a single lymphocyte lineage was challenged, however, by observations in other vertebrate species. One important discovery, which was made by poultry scientists in 1956, went unnoticed by most contemporary immunologists. In addition to having a thymus, birds have a lymphoid organ called the bursa of Fabricius, sometimes nicknamed the “cloacal thymus” because of its location above the cloaca and its histological appearance. A postulated endocrine role of the bursa was not supported by the normal growth and sexual development of chicks following early bursectomy, but severe impairment of antibody responses was fortuitously discovered in these bursa-less birds. Testosterone treatment of chick embryos also inhibited bursa development and antibody production, and this “chemical bursectomy” sometimes impaired thymus development as well. Subsequent studies suggested the avian thymus and bursa could differentially influence cellular and humoral immune functions, but the functional effects of early thymectomy were inconsistent in different chicken strains and difficult to correlate with related studies in mammals.

Patients with familial immunodeficiency diseases offered additional insight into immune system development. Boys who had recurrent bacterial infections because of congenital agammaglobulinemia were noted to be deficient in germinal centers and plasma cells, although their thymus and lymphocyte levels were normal, and they could control most virus infections. Conversely, boys with Wiskott-Aldrich syndrome (frequent ear infections, eczema, and platelet deficiency) were found to have an atrophic thymus, severe lymphocyte deficiency, and inability to survive herpes simplex virus infection, despite having an abundance of plasma cells and their immunoglobulin products.

These findings, which were not consistent with the single lymphocyte lineage model, led to a revisit of the avian model, but this time with near-lethal whole-body irradiation in addition to thymus or bursa removal at hatching in order to destroy immune cells that might have developed earlier. When the birds that had been thymectomized and irradiated were examined after recovery from irradiation several weeks later, they were deficient in lymphocytes, rejected foreign skin grafts slowly, and failed to develop delayed-type hypersensitivity; antibody responses were modestly impaired, and they had germinal centers and plasma cells. Conversely, the birds that had been bursectomized and irradiated produced no germinal centers, plasma cells, or antibodies, although their thymus development, lymphocyte levels, and cellular immunity responses were normal.4,5 Moreover, infusion of their nonirradiated bursa lymphocytes restored germinal centers, plasma cells, and immunoglobulin production.6

These results were indicative of 2 distinctive lineages of lymphocytes, a thymus-dependent lineage of lymphocytes that was primarily responsible for cellular immunity and a bursa-dependent lineage of cells that was responsible for antibody production and humoral immunity. Contemporaneous studies defining hematopoietic stem cells suggested these could be the precursors of both lymphocyte lineages. Validation of this compartmentalized model of lymphocyte development in humans was provided by the plasma cell development and antibody production observed in congenitally athymic patients.

Experiments in which the techniques of thymectomy, irradiation, and inoculation of genetically marked cells from the lymph and from bone marrow were combined indicated that thymus-derived cells (now called T cells) were not antibody-producing cells, but helped other lymphocytes derived from bone marrow (now called B cells) to produce antibody.7 Collectively, these findings established that the adaptive immune system is based on 2 universes of lymphocytes, one T-cell dependent and responsible for cellular immunity, as in graft rejection and in the control of virus infections, the other B-cell dependent and involved in humoral immunity by means of antibody secretion.

A search for the origin of adaptive immunity has shown that the basic genetic program for the T and B lineages of lymphocytes is conserved in both jawed and jawless vertebrates and thus already existed in a common vertebrate ancestor approximately 500 million years ago.8 For antigen recognition, however, lymphocytes in the jawless vertebrates (lampreys and hagfish) use highly variable lymphocyte receptors encoded by leucine-rich-repeat gene segments instead of immunoglobulin gene segments.

In recent years, it has been shown that T cells are involved essentially across the entire spectrum of tissue physiology and pathology, not just in reactions or diseases considered to be bona fide immunological, but also, to cite just some examples, in metabolism, in tissue repair, in dysbiosis, and in pregnancy. Basic research on T cells has also sown the seeds that spawned the new era of immunotherapy that is engaging numerous researchers in finding a cure for cancer.

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Article Information

Corresponding Author: Max Dale Cooper, MD, Emory University School of Medicine, 1462 Clifton Rd, DSB 403C, Atlanta, GA 30322 (mdcoope@emory.edu).

Published Online: September 10, 2019. doi:10.1001/jama.2019.13815

Conflict of Interest Disclosures: Dr Cooper reported receiving grants from the National Institutes of Health, Howard Hughes Medical Institute, and Georgia Research Alliance; being the cofounder of NovAb; and having the following patents: “Methods and Compositions Related to Soluble Monoclonal Variable Lymphocyte Receptors of Defined Antigen Specificity,” “Modified Recombinant Variable Lymphocyte Receptors,” and “Expression of Chimeric Polypeptide with Variable Lymphocyte Receptors on Immune Cells and Uses for Treating Cancer.” No other disclosures were reported.

References
1.
Miller  JF.  Immunological function of the thymus.  Lancet. 1961;2(7205):748-749. doi:10.1016/S0140-6736(61)90693-6PubMedGoogle ScholarCrossref
2.
Miller  JF.  Effect of neonatal thymectomy on the immunological responsiveness of the mouse.  Proc Roy Soc. 1962;156B:410-428.Google Scholar
3.
Miller  JF.  Immunological significance of the thymus of the adult mouse.  Nature. 1962;195:1318-1319. doi:10.1038/1951318a0Google ScholarCrossref
4.
Cooper  MD, Peterson  RDA, Good  RA.  Delineation of the thymic and bursal lymphoid systems in the chicken.  Nature. 1965;205:143-146. doi:10.1038/205143a0PubMedGoogle ScholarCrossref
5.
Cooper  MD, Raymond  DA, Peterson  RD, South  MA, Good  RA.  The functions of the thymus system and the bursa system in the chicken.  J Exp Med. 1966;123(1):75-102. doi:10.1084/jem.123.1.75PubMedGoogle ScholarCrossref
6.
Cooper  MD, Schwartz  ML, Good  RA.  Restoration of gamma globulin production in agammaglobulinemic chickens.  Science. 1966;151(3709):471-473. doi:10.1126/science.151.3709.471PubMedGoogle ScholarCrossref
7.
Mitchell  GF, Miller  JF.  Cell to cell interaction in the immune response, II: the source of hemolysin-forming cells in irradiated mice given bone marrow and thymus or thoracic duct lymphocytes.  J Exp Med. 1968;128(4):821-837. doi:10.1084/jem.128.4.821PubMedGoogle ScholarCrossref
8.
Hirano  M, Guo  P, McCurley  N,  et al.  Evolutionary implications of a third lymphocyte lineage in lampreys.  Nature. 2013;501(7467):435-438. doi:10.1038/nature12467PubMedGoogle ScholarCrossref
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