Thymus Development

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Introduction

Embryonic origins of the endocrine organs of the neck
Adult thymus location

The thymus has a key role in the development of an effective immune system as well as an endocrine function.

The thymus has two origins for the lymphoid thymocytes and the thymic epithelial cells. The thymic epithelium begins as two flask-shape endodermal diverticula that form from the third pharyngeal pouch and extend lateralward and backward into the surrounding mesoderm and neural crest-derived mesenchyme in front of the ventral aorta. The immune system T cells are essential for responses against infections and much research concerns the postnatal development of T cells within the thymus.

The mature thymus epithelium has two main cell types: cortical thymic epithelial (cTECs) and medullary thymic epithelial cells (mTECs) or stromal cells. These thymic stromal cells provide signals for T cell differentiation.


Endocrine Links: Introduction | BGD Lecture | Science Lecture | Pineal | Hypothalamus‎ | Pituitary | Thyroid | Parathyroid | Thymus‎ | Pancreas‎ | Adrenal‎ | Gonad‎ | Placenta‎ | Other Tissues | Stage 22 | Abnormalities | Hormones | Category:Endocrine


Immune Links: Introduction | Blood | Spleen | Thymus | Lymphatic | Lymph Node | Antibody | Med Lecture - Lymphatic Structure | Med Practical | Immune Movies | Vaccination | Bacterial Infection | Category:Immune
Historic Embryology
1912 Development of the Lymphatic System | 1918 Gray's Lymphatic Images | 1916 Pig Lymphatics | 1919 Chicken Lymphatic | 1922 Pig Stomach Lymphatics | Historic Disclaimer

Some Recent Findings

Mouse Thymus gene expression[1]
  • Dynamics of thymus organogenesis and colonization in early human development[2] "The thymus is the central site of T-cell development and thus is of fundamental importance to the immune system, but little information exists regarding molecular regulation of thymus development in humans. ... In addition, we provide molecular evidence that the human thymic epithelium derives solely from the third pharyngeal pouch, as in the mouse, in contrast to previous suggestions."
  • Thymus organogenesis[3]"A new study in the jawless fish, lampreys, indicates the existence of a primitive thymus in these surviving representatives of the most ancient vertebrates, providing strong evidence of co-evolution of T cells and thymus."
  • Modulation of Bmp4 signalling in the epithelial-mesenchymal interactions that take place in early thymus and parathyroid development in avian embryos[4] "Epithelial-mesenchymal interactions are crucial for the development of the endoderm of the pharyngeal pouches into the epithelia of thymus and parathyroid glands. ...Furthermore, mesenchymal-derived Bmp4 appears to be essential to promote early stages of endoderm development during a short window of time, irrespective of the mesenchymal source. In vivo studies using the quail-chick system and implantation of growth factor soaked-beads further showed that expression of Bmp4 by the mesenchyme is necessary during a 24 h-period of time. After this period however, Bmp4 is no longer required and another signalling factor produced by the mesenchyme, Fgf10, influences later differentiation of the pouch endoderm. "

Development Overview

Stage 13 Embryo pharyngeal arches showing 3rd pharyngeal pouch

The thymus and parathyroid are derived from 3rd pharyngeal pouches.

Development is a series of epithelial/mesenchymal inductive interactions between neural crest-derived arch mesenchyme and pouch endoderm. There is also the possibility that the surface ectoderm of 3rd pharyngeal clefts participates in thymus development.

Thymic epithelial cells (TECs) are derived from the endoderm of the third pharyngeal pouch.

Hassall's bodies form between 6 and 10 lunar months in humans. They appear after lymphopoiesis has been established and the cortex, medulla and the cortico-medullary junction are able to select of T lymphocytes undergoing progressive maturation. (Text modified from Bodey and Kaiser, 1997)

Experimental studies have shown that a neural crest contribution is also required during early thymic organogenesis.

Week 8

Late embryonic thymus development.

Stage 22 image 200.jpg Human- Stage 22 thymus 01.jpg
Image shows general position of the developing thymus in entire embryo cross-section. The developing thymus is shown in the midline, located behind the sternum (right) and in front of the oesophagus and trachea. Selected high power image of thymus from complete cross-section above.


Links: Carnegie stage 22

Development Changes

Fetal thymus anatomy
Fetal thymus
Fetal thymus weight growth graph.jpg

Human Fetal Thymus Weight Growth

Overall Size Changes with age
  • birth 10-15 g
  • puberty 30-40 g
  • after puberty - involution
    • Replaced by adipose tissue
    • middle-aged 10 g

Thymus Anatomy

  • Superior mediastinum, anterior to heart
  • Bilobed lymphoepithelial organ
    • Contains reticular cells but no fibers
  • Stem lymphocytes
    • proliferate and differentiate
    • forms long-lived T- lymphocytes

Thymus Cells

Thymus Histology: Fetal Thymus overview | Fetal Thymus Medulla | Fetal Thymus Cortex | Adult Thymus | unlabeled fetal overview | unlabeled fetal medulla |unlabeled fetal thymic corpuscle |unlabeled fetal cortex | unlabeled adult overview | Category:Thymus | Immune System Development
  • Reticular cells
    • Abundant, eosinophilic, large, ovoid and light nucleus 1-2 nucleoli
    • sheathe cortical capillaries
    • form an epitheloid layer
    • maintain microenvironment for development of T-lymphocytes in cortex (thymic epitheliocytes)
  • Macrophages
    • cortex and medulla
    • difficult to distinguish from reticular cells in H&E
  • Lymphocytes
    • cortex and medulla - more numerous (denser) in cortex
    • majority of them developing T-lymphocytes (= thymic lymphocytes or thymocytes)

T Lymphocyte

The following images are electron micrographs of T Lymphocyte (T cell) at different stages.

Lymphocyte EM Images: T and B Lymphocytes 1 TEM | T and B Lymphocytes 2 TEM | T Lymphocyte SEM | B lymphocyte 1 TEM | B lymphocyte 2 TEM | B lymphocyte 3 TEM | Plasma Cell TEM | T2 Lymphocyte 1 TEM | T2 Lymphocyte 2 TEM | lymphocyte rosettes | T lymphocyte 1 | T lymphocyte 2 | T lymphocyte 3 | T lymphocyte 4 | T lymphocyte 5 | T lymphocyte 6 | B lymphocyte | B lymphocytes TEM | Immune System Development

Fetal/Young Thymus

Thymus - young 01.jpg Thymus - young 02.jpg
Young medulla Young cortex

Thymic corpuscle

Hassall’s corpuscle - Mass of concentric epithelioreticular cells

Thymus Involution

Thymus adult.jpg

Adult Thymus Histology

A postnatal process defined as a decrease in the size, weight and activity of the gland with advancing age.
  • After puberty much of the parenchyma of the thymus is replaced by adipose tissue.
  • particularly cortical lymphoid tissue.
  • initially proceeds rapid but slows down in adulthood.
  • Increase in size of thymic corpuscles.
  • process is called involution
  • under the control of steroid hormones

In a recent review[5], thymic involution was described as a result of high levels of circulating sex hormones, in particular during puberty, and a lower population of precursor cells from the bone marrow and finally changes in the thymic microenvironment.

Hassall's Bodies

Fetal thymus showing Hassall's body

Hassall's bodies, also called Hassall's corpuscles

  • form between 6 and 10 lunar months in humans.
  • appear after lymphopoiesis has been established and the cortex, medulla and the cortico-medullary junction are able to select of T lymphocytes undergoing progressive maturation.
  • within the thymus their number increases until puberty, then decreases.
  • features are named after Arthur Hill Hassall (1817-1894) a British physician and chemist.

Function

Thymus Hassall's corpuscle.jpg

Hassall's corpuscles express thymic stromal lymphopoietin (TSLP), suggesting that Hassall's corpuscles have a critical role in dendritic-cell-mediated secondary positive selection of medium-to-high affinity self-reactive T cells, leading to the generation of CD4(+)CD25(+) regulatory T cells within the thymus.[6]

Thymic stromal lymphopoietin is an epithelial cell-derived cytokine expressed in several tissues (skin, gut, lungs, and thymus) that signals through a TSLP receptor (TSLPR). This receptor is a heterodimer of the IL-7 receptor alpha chain and the TSLPR chain.

Disease Association

There has been one report showing changes in Hassall's bodies morphology associated with congenital heart defects.[7]

Histology

Thymus Histology: Fetal Thymus overview | Fetal Thymus Medulla | Fetal Thymus Cortex | Adult Thymus | unlabeled fetal overview | unlabeled fetal medulla |unlabeled fetal thymic corpuscle |unlabeled fetal cortex | unlabeled adult overview | Category:Thymus | Immune System Development

The developing fetal thymus shown below is from a 20 week gestational age (GA), 18 week post-fertilization age, or second trimester stage of development.

Molecular Development

Mouse Thymus gene expression[1]
Mouse Thymus E9.5 and E10.5[1]
Mouse Thymus E11[1]

Foxg1 and Isl1

Transcription factors that appear to have a role in early thymic epithelial cell (TEC) differentiation

Foxn1

Cited2

Cited2 deletion in the mouse is embryonic lethal with cardiovascular malformations, adrenal agenesis, cranial ganglia fusion, exencephaly, and left-right patterning defects.[8]

"Examination of Lmo4-deficient embryos revealed partially penetrant cardiovascular malformations and hypoplastic thymus. Examination of Lmo4;Cited2 compound mutants indicated that there is a genetic interaction between Cited2 and Lmo4 in control of thymus development. Our data suggest that this may occur, in part, through control of expression of a common target gene, Tbx1, which is necessary for normal thymus development."

Eva and Six

Both Eva and Six have been implicated in thymus development.[9]

  • Eya - human homolog of the Drosophila 'eyes absent' (Eya) gene.
  • Six - vertebrate genes which are homologs of the Drosophila 'sine oculis' (so) gene.

References

  1. 1.0 1.1 1.2 1.3 Qiaozhi Wei, Brian G Condie A focused in situ hybridization screen identifies candidate transcriptional regulators of thymic epithelial cell development and function. PLoS ONE: 2011, 6(11);e26795 PMID: 22087235 | PLoS One.
  2. Alison M Farley, Lucy X Morris, Eric Vroegindeweij, Marianne L G Depreter, Harsh Vaidya, Frances H Stenhouse, Simon R Tomlinson, Richard A Anderson, Tom Cupedo, Jan J Cornelissen, C Clare Blackburn Dynamics of thymus organogenesis and colonization in early human development. Development: 2013, 140(9);2015-26 PMID: 23571219
  3. Qing Ge, Yong Zhao Evolution of thymus organogenesis. Dev. Comp. Immunol.: 2011, 39(1-2);85-90 PMID: 22266420
  4. Hélia Neves, Elisabeth Dupin, Leonor Parreira, Nicole M Le Douarin Modulation of Bmp4 signalling in the epithelial-mesenchymal interactions that take place in early thymus and parathyroid development in avian embryos. Dev. Biol.: 2012, 361(2);208-19 PMID: 22057081
  5. Victor Appay, Delphine Sauce, Martina Prelog The role of the thymus in immunosenescence: lessons from the study of thymectomized individuals. Aging (Albany NY): 2010, 2(2);78-81 PMID: 20354268
  6. Norihiko Watanabe, Yi-Hong Wang, Heung Kyu Lee, Tomoki Ito, Yui-Hsi Wang, Wei Cao, Yong-Jun Liu Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature: 2005, 436(7054);1181-5 PMID: 16121185
  7. I Varga, V Pospisilova, V Jablonska, V Sisovsky, P Galfiova, S Polak, M Adamkov Thymic Hassall's bodies of children with congenital heart defects. Bratisl Lek Listy: 2010, 111(10);552-7 PMID: 21125801
  8. Anna C Michell, José Bragança, Carol Broadbent, Bradley Joyce, Angela Franklyn, Jürgen E Schneider, Shoumo Bhattacharya, Simon D Bamforth A novel role for transcription factor Lmo4 in thymus development through genetic interaction with Cited2. Dev. Dyn.: 2010, 239(7);1988-94 PMID: 20549734
  9. Dan Zou, Derek Silvius, Julie Davenport, Raphaelle Grifone, Pascal Maire, Pin-Xian Xu Patterning of the third pharyngeal pouch into thymus/parathyroid by Six and Eya1. Dev. Biol.: 2006, 293(2);499-512 PMID: 16530750

Reviews

Thomas Boehm, Jeremy B Swann Thymus involution and regeneration: two sides of the same coin? Nat. Rev. Immunol.: 2013, 13(11);831-8 PMID: 24052146

Julie Gordon, Nancy R Manley Mechanisms of thymus organogenesis and morphogenesis. Development: 2011, 138(18);3865-78 PMID: 21862553

Thomas Boehm Thymus development and function. Curr. Opin. Immunol.: 2008, 20(2);178-84 PMID: 18403191

Wilson Savino The thymus is a common target organ in infectious diseases. PLoS Pathog.: 2006, 2(6);e62 PMID: 16846255

Georg Holländer, Jason Gill, Saulius Zuklys, Norimasa Iwanami, Cunlan Liu, Yousuke Takahama Cellular and molecular events during early thymus development. Immunol. Rev.: 2006, 209;28-46 PMID: 16448532

Thomas Boehm, Conrad C Bleul, Michael Schorpp Genetic dissection of thymus development in mouse and zebrafish. Immunol. Rev.: 2003, 195;15-27 PMID: 12969307

J Sen Signal transduction in thymus development. Cell. Mol. Biol. (Noisy-le-grand): 2001, 47(1);197-215 PMID: 11292256


Articles

Adrienne E Calder, Melanie N Hince, Jarrod A Dudakov, Ann P Chidgey, Richard L Boyd Thymic involution: where endocrinology meets immunology. Neuroimmunomodulation: 2011, 18(5);281-9 PMID: 21952680

A Cromi, F Ghezzi, R Raffaelli, V Bergamini, G Siesto, P Bolis Ultrasonographic measurement of thymus size in IUGR fetuses: a marker of the fetal immunoendocrine response to malnutrition. Ultrasound Obstet Gynecol: 2009, 33(4);421-6 PMID: 19306477

Yaron Zalel, Ronni Gamzu, Shlomo Mashiach, Reuven Achiron The development of the fetal thymus: an in utero sonographic evaluation. Prenat. Diagn.: 2002, 22(2);114-7 PMID: 11857615


Search PubMed: Thymus Development | Thymus Embryology

Terms

  • Cytotoxic T lymphocytes - (CTLs, killer T cells) directly attack other cells carrying certain foreign or abnormal molecules on their surfaces including attacking viruses, that hide from other parts of the immune system growing inside infected cells.
  • Helper T cells - (Th cells) coordinate immune responses by communicating with other cells. Some stimulate nearby B cells to produce antibodies, others call in phagocytes, and still others activate other T cells.

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Cite this page: Hill, M.A. (2014) Embryology Thymus Development. Retrieved October 25, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Thymus_Development

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© Dr Mark Hill 2014, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G