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• W2019911933 abstract "The thymus is required for the differentiation of T lymphocytes. A new study in lampreys indicates that the pharyngeal epithelium of the gill basket supports the development of T-like cells, suggesting the existence of a primitive thymus in these oldest of vertebrates. The thymus is required for the differentiation of T lymphocytes. A new study in lampreys indicates that the pharyngeal epithelium of the gill basket supports the development of T-like cells, suggesting the existence of a primitive thymus in these oldest of vertebrates. In most jawed vertebrates (gnathostomes), B cells and the majority of other hematopoietic cell lineages develop in the bone marrow or its equivalent. By contrast, T cells develop in a specialized organ known as the thymus, which is derived from the endoderm of the pharyngeal arches. In many cultures, the thymus of calves or lambs is eaten with relish and is known as ‘sweetbreads’. Since its discovery as the indispensable organ for T-cell development by Jacques Miller in the early 1960s [1Miller J.F.A.P. Immunological function of the thymus.Lancet. 1961; 2: 748-749Abstract PubMed Scopus (705) Google Scholar], the thymus has been studied extensively for its roles in the positive and negative selection of immature T cells with some uniquely spectacular findings [2Klein L. Hinterberger M. Wirnsberger G. Kyewski B. Antigen presentation in the thymus for positive selection and central tolerance induction.Nat. Rev. Immunol. 2009; 9: 833-844Crossref PubMed Scopus (368) Google Scholar]. For example, a transcription factor called AIRE is expressed by the thymic medulla and is responsible (in ways that remain rather mysterious) for promoting expression of tissue-specific genes (e.g. pancreatic insulin), so that developing self-reactive T cells can be exposed to self-antigens and then disposed of before being sent to the periphery [3Anderson M.S. Venanzi E.S. Klein L. Chen Z. Berzens S.P. Turley S.J. von Boehmer H. Bronson R. Dierich A. Benoist C. et al.Projection of a self shadow within the thymus by the aire protein.Science. 2002; 298: 1395-1401Crossref PubMed Scopus (1757) Google Scholar]. Positive selection for ‘useful’ T cells, i.e. those cells capable of recognizing antigen in association with self major histocompatibility complex (MHC) molecules, occurs when developing lymphocytes interact with self-MHC–self-peptide complexes displayed on the surface of thymic epithelial cells. It has been shown recently that a thymic-specific proteasome component called β5t seems to be required for the selection of CD8+ T cells, suggesting that a specific subset of peptides is generated which positively selects the useful T cells [4Murata S. Sasaki K. Kishimoto T. Niwa S. Hayashi H. Takahama Y. Tanaka K. Regulation of CD8+ T cell development by thymus-specific proteasomes.Science. 2007; 316: 1349-1353Crossref PubMed Scopus (401) Google Scholar]. Now, in a recent Nature paper, Boehm and colleagues [5Bajoghli B. Guo P. Aghaallaei N. Hirano M. Strohmeier C. McCurley N. Bockman D.E. Schorpp M. Cooper M.D. Boehm T. Identification of a thymus candidate in lampreys.Nature. 2011; 470: 90-94Crossref PubMed Scopus (149) Google Scholar] report a thymus-like structure in lampreys, which seems to offer the evolutionarily oldest, and perhaps original, example of this T-cell-selecting environment. The thymus appeared in evolution with the emergence of adaptive immunity in the extinct placoderm lineage ∼500 million years ago [6Flajnik M.F. Du Pasquier L. Evolution of the immune system.in: Paul W.E. Fundamental Immunology. 6th ed. Lippincott, Williams, & Wilkins, Philadelphia2008Google Scholar]. There has never been any controversy concerning the presence of a thymus in all living jawed vertebrates from cartilaginous fish (sharks) to mammals (humans), and its requirement for T-cell differentiation is universal. The lack of a thymus in the oldest vertebrates — the jawless fish (lampreys and hagfishes) — was consistent with the reported deficiency in adaptive immunity in these animals. Even when an entirely new type of adaptive immune system was detected in jawless fish that centered on a novel antigen receptor family generated by somatic rearrangement and expressed by lymphocytes — the so-called variable lymphocyte receptors or VLR [7Pancer Z. Amemiya C.T. Ehrhardt G.R.A. Ceitlin J. Gartland G.L. Cooper M.D. Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey.Nature. 2004; 430: 174-180Crossref PubMed Scopus (500) Google Scholar] — it still seemed unlikely that there was a dichotomy of lymphocytes, and hence there was believed to be no requirement for a thymus. In fact, a series of experiments following the immunization of larval lampreys suggested that the jawless vertebrate adaptive system might be dedicated exclusively to humoral immunity, with pattern-associated molecular patterns (PAMPs) providing a second signal to activate lymphocytes [8Alder M.N. Herrin B.R. Sadlonova A. Stockard C.R. Grizzle W.E. Gartland G.L. Boydston J.A. Turnbough Jr., C.L. Cooper M.D. Antibody responses of variable lymphocyte receptors in sea lamprey.Nat. Immunol. 2008; 9: 319-327Crossref PubMed Scopus (133) Google Scholar]. Thus, it was proposed that the lamprey system was B-cell-centric and therefore focused on humoral immunity. However, subsequent work demonstrated that there were two types of VLR in the jawless fish, VLRA and VLRB [9Rogozin I.B. Lakshminarayan M.I. Liang L. Glazko G.V. Liston V.G. Pavlov Y.I. Aravind L. Pancer Z. Evolution and diversification of lamprey antigen receptors: evidence for involvement of an AID-APOBEC family cytosine deaminase.Nat. Immunol. 2007; 8: 647-656Crossref PubMed Scopus (225) Google Scholar, 10Guo P. Hirano M. Herrin B.R. Li J. Yu C. Sadlonova A. Cooper M.D. Dual nature of the adaptive immune system in lampreys.Nature. 2009; 459: 796-801Crossref PubMed Scopus (253) Google Scholar]. The former receptor could not be found in plasma and seemed to be expressed exclusively as a cell-surface receptor on lymphocytes, while the latter was present as both a lymphocyte receptor and a secreted molecule [10Guo P. Hirano M. Herrin B.R. Li J. Yu C. Sadlonova A. Cooper M.D. Dual nature of the adaptive immune system in lampreys.Nature. 2009; 459: 796-801Crossref PubMed Scopus (253) Google Scholar]. Remarkably, the lamprey adaptive scheme parallels the situation in jawed vertebrates where immunoglobulin is found both as a cell-surface receptor on B cells and as a secreted effector molecule in the serum, whereas the T-cell receptor is present only as a cell-surface receptor on T cells; effector functions in T cells, such as cytokine secretion or production of cytotoxic mediators, are properties of the T cells themselves. Amazingly, when microarray expression analysis was performed on VLRA and VLRB positive cells, the patterns fit rather well with expression profiles in gnathostome T cells and B cells, respectively [10Guo P. Hirano M. Herrin B.R. Li J. Yu C. Sadlonova A. Cooper M.D. Dual nature of the adaptive immune system in lampreys.Nature. 2009; 459: 796-801Crossref PubMed Scopus (253) Google Scholar]! This finding heralded the renewed search for a thymus equivalent in lampreys, as reported in the new paper [5Bajoghli B. Guo P. Aghaallaei N. Hirano M. Strohmeier C. McCurley N. Bockman D.E. Schorpp M. Cooper M.D. Boehm T. Identification of a thymus candidate in lampreys.Nature. 2011; 470: 90-94Crossref PubMed Scopus (149) Google Scholar]. Indeed, there was an extensive literature on this topic over the past century identifying accumulations of cells in various cranial regions, suggesting that lymphocytes could be differentiating in these areas. However, it has always been clear that there is no specialized tissue with a defined cortex and medulla in lampreys or hagfish as is seen in all gnathostomes (Figure 1). Of course, this conclusion was premature since there were no molecular markers for either lymphocytes or thymic epithelium in jawless fish, so we were left to wonder. In fact, the major author of the recent Nature paper had concluded in a previous Cell paper [11Bajoghli B. Aghaallaei N. Hess I. Rode I. Netuschil N. Tay B.-H. Venkatesh B. Yu J.-K. Kaltenbach S.L. Holland N.D. et al.Evolution of genetic networks underlying the emergence of thymopoiesis in vertebrates.Cell. 2009; 138: 186-197Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar] that there was ‘no evidence for a thymus in lampreys’. In that earlier work [11Bajoghli B. Aghaallaei N. Hess I. Rode I. Netuschil N. Tay B.-H. Venkatesh B. Yu J.-K. Kaltenbach S.L. Holland N.D. et al.Evolution of genetic networks underlying the emergence of thymopoiesis in vertebrates.Cell. 2009; 138: 186-197Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar], a major transcription factor involved in the development of T cells, foxn1, was found to be expressed by the pharyngeal epithelium, but the lack of expression of any known lymphocyte markers meant that it was unlikely that this region was truly the thymus equivalent; a similar transcription profile was seen in the gill epithelium of the model basal chordate Amphioxus, which (apparently!) truly lacks an adaptive immune system. The celebrated quote from Mark Twain — “the report of my death was an exaggeration” — fits well here. The discovery of ‘T cells’ in lampreys opened a new panorama with the expression of additional T-cell-specific genes besides the antigen receptors [10Guo P. Hirano M. Herrin B.R. Li J. Yu C. Sadlonova A. Cooper M.D. Dual nature of the adaptive immune system in lampreys.Nature. 2009; 459: 796-801Crossref PubMed Scopus (253) Google Scholar]. In 2007, Pancer and colleagues [9Rogozin I.B. Lakshminarayan M.I. Liang L. Glazko G.V. Liston V.G. Pavlov Y.I. Aravind L. Pancer Z. Evolution and diversification of lamprey antigen receptors: evidence for involvement of an AID-APOBEC family cytosine deaminase.Nat. Immunol. 2007; 8: 647-656Crossref PubMed Scopus (225) Google Scholar] discovered that lamprey lymphocytes express two genes encoding APOBEC-like cytidine deaminases — CDA1 and CDA2 — and suggested that they were involved in the rearrangement (and perhaps mutational) events in the VLR genes. Later work led to the suggestion that these APOBEC family members were expressed specifically in either VLRA (CDA1) or VLRB (CDA2) cells [10Guo P. Hirano M. Herrin B.R. Li J. Yu C. Sadlonova A. Cooper M.D. Dual nature of the adaptive immune system in lampreys.Nature. 2009; 459: 796-801Crossref PubMed Scopus (253) Google Scholar]. Now, in the new Nature paper [5Bajoghli B. Guo P. Aghaallaei N. Hirano M. Strohmeier C. McCurley N. Bockman D.E. Schorpp M. Cooper M.D. Boehm T. Identification of a thymus candidate in lampreys.Nature. 2011; 470: 90-94Crossref PubMed Scopus (149) Google Scholar], CDA1 is shown to be expressed by lymphocytes in close proximity to the foxn1-positive pharyngeal epithelial cells (Figure 1). Furthermore, only in these ‘developing’ lymphocytes, but not in mature VLRA-positive cells, could a high percentage (∼25%) of out-of-frame VLRA genes be detected, implying that cells were differentiating in this region. In summary, this tissue in lampreys, which was christened the ‘thymoid’, is derived from the pharyngeal epithelium, expresses classical thymic epithelial markers such as foxn1 and Notch ligands, and is associated with developing VLRA cells, based on the expression of the APOBEC family member CDA1, presence of out-of-frame VLRA gene sequences, and failure to respond to activation signals (such as the T-cell mitogen phytohemagglutinin) that stimulate mature lymphocytes. In addition, consistent with the high percentage of cells with a non-functional receptor, many lymphocytes were observed to undergo apoptosis in the thymoid, which is also comparable to the situation in jawed vertebrates. Much more work is necessary to understand this system, but the basic finding is extraordinary and will certainly attract immunologists and developmental biologists to study this problem further. In all other vertebrates, early thymectomy results in profound immunodeficiency [6Flajnik M.F. Du Pasquier L. Evolution of the immune system.in: Paul W.E. Fundamental Immunology. 6th ed. Lippincott, Williams, & Wilkins, Philadelphia2008Google Scholar]. Since the thymoid is expressed at the tips of all of the gill filaments (Figure 1), thymectomy will not be possible in jawless fish. Perhaps procedures will be developed to block the interactions between the VLRA cells and the pharyngeal epithelium, or to disrupt the development of the thymoid itself. Assuming that this tissue indeed is the thymic equivalent in lampreys, what is the significance of having the VLRA cells develop in a unique organ? In gnathostomes, T cells recognize antigen in the form of peptides in association with MHC class I or class II molecules. As mentioned above, because of the high levels of MHC polymorphism, T cells are positively selected in the thymus for cells that recognize antigen in association with the thymic MHC. Despite major effort, neither MHC molecules nor the specialized proteins associated with antigen processing have been detected in the jawless fish [12Uinuk-Ool T. Mayer W.E. Sato A. Dongak R. Cooper M.D. Klein J. Lamprey lymphocyte-like cells express homologues of genes involved in immunologically relevant activities of mammalian lymphocytes.Proc. Natl. Acad. Sci. USA. 2002; 99: 14356-14361Crossref PubMed Scopus (121) Google Scholar], and thus, if there is positive selection, it must be orchestrated by a convergent system of antigen processing/presentation. In the same vein, perhaps there is an AIRE equivalent expressed by the thymoid that ensures deletion of self-reactive clones; if so, it would also imply that a convergent antigen presentation system will be discovered in lampreys. I think it will be of interest to re-examine differentiation of lymphocytes in the pharyngeal epithelium of basal chordates [11Bajoghli B. Aghaallaei N. Hess I. Rode I. Netuschil N. Tay B.-H. Venkatesh B. Yu J.-K. Kaltenbach S.L. Holland N.D. et al.Evolution of genetic networks underlying the emergence of thymopoiesis in vertebrates.Cell. 2009; 138: 186-197Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar]; perhaps this will lead us to an understanding of the origins of adaptive immunity in the vertebrates. Finally, what is the significance of T cells developing in association with the pharyngeal epithelium? Is it because this area in the gill region is evolutionarily plastic or is there some relevance to exposure of the thymoid to the external environment? Most comparative immunologists never expected a unique antigen receptor system to be uncovered in jawless fish [7Pancer Z. Amemiya C.T. Ehrhardt G.R.A. Ceitlin J. Gartland G.L. Cooper M.D. Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey.Nature. 2004; 430: 174-180Crossref PubMed Scopus (500) Google Scholar]. To then realize that the divergence of lymphocytes into two lineages occurred in the ancestor of jawed and jawless fish was astonishing [10Guo P. Hirano M. Herrin B.R. Li J. Yu C. Sadlonova A. Cooper M.D. Dual nature of the adaptive immune system in lampreys.Nature. 2009; 459: 796-801Crossref PubMed Scopus (253) Google Scholar]. Now to have uncovered a primitive type of thymus candidate in jawless fish is a metaphorical kick in the solar plexus [5Bajoghli B. Guo P. Aghaallaei N. Hirano M. Strohmeier C. McCurley N. Bockman D.E. Schorpp M. Cooper M.D. Boehm T. Identification of a thymus candidate in lampreys.Nature. 2011; 470: 90-94Crossref PubMed Scopus (149) Google Scholar]. All of these discoveries force us to acknowledge that we should not be surprised by future discoveries in the evolution of immunity, such as a ‘convergent MHC’ or a primordial type of adaptive immune system in lower deuterostomes or protostomes. Take it from me, sweetbreads are delicious, especially when prepared lightly fried in the Latin American fashion. However, these discoveries in the adaptive immune system of lampreys provide much more than the passing delight of exquisite cuisine; rather they tantalize the intellect and compel us to wonder whether future breakthroughs will not only expand our joy at the wonders of nature, but also further illuminate the basic mechanisms of lymphocyte (and embryological) development." @default.
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