The Thymus as The Primary Site of T-cell Production

The Thymus as The Primary Site of T-cell Production

Thymus Histology Lobulated organ with outer cortex and inner medulla C M

Ordered Microenvironments Support T-cell Development CD4-CD8- precursors CD4+CD8+ intermediates CORTEX MHC I CD4+CD8- Helper T-cells CD4-CD8+ Cytolytic T-cells MHC II MEDULLA

T-Cells Are Educated To Recognise MHC In The Thymus T-cell Dendritic Cell Unlike B-cells, T-cells recognise processed Antigen presented by self Major Histocompatibility Complex (MHC) molecules Development in the Thymus: TCR gene rearrangement is random, so specificities can be: USELESS HARMFUL USELESS Need to: Retain USEFUL specificities (POSITIVE SELECTION) Remove HARMFUL specificities (NEGATIVE SELECTION)

Selecting a Self-Tolerant T-cell Receptor Repertoire Positive Selection: Ensures survival of thymocytes with TCRs which recognise self-mhc but which are not autoreactive Negative Selection: Purges the immature TCR repertoire of potentially autoreactive specificities CD4+25+ Regulatory T-cell production in the thymus

How is Tolerance to Tissue-Specific Antigens Achieved? Is there such a thing as a tissue specific antigen? Intrathymic expression of proteins usually made in: central nervous system, pancreas, thyroid, salivary gland: Promiscuous gene expression

How is Tolerance to Tissue-Specific Antigens Achieved? Tissue specific antigens are expressed by thymic medullary epithelial cells (Derbinksi et al Nat. Immunol. 2001 2:1032 GAD67 (CNS) Insulin (Pancreas)

Thymus Mirrors Peripheral Self? X X X Peripheral Organs

What Regulates Peripheral Gene Expression In The Thymus? AIRE and multi-organ autoimmunity APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) First systemic (bodywide) autoimmune disease found to be due to a defect in a single gene Aire and The Thymus Aire is a transcription factor expressed by thymic medullary epithelial cells.

How is Tolerance to Tissue-Specific Antigens Achieved? AIRE- knockout mice show a reduction in tissue-specific gene expression in the thymus (Anderson et al Science 2002 Vol 298 p1398) AIRE knockout Wildtype

How is Tolerance to Tissue-Specific Antigens Achieved? This correlates with organ-specific autoimmunity Serum from AIRE knockout Serum from Wildtype

Conclusions/References Self-tolerance is imposed in the thymus Expression of peripheral antigens in the thymus is regulated partly by AIRE Curr. Opin. Immunol. 2004 16:741-5. Nat. Rev. Immunol. 2004 4:688-98.

Thymic Atrophy Results In An Age-Related Decrease In T-cell Production Number of New T-cells produced per day 0 Age in years 70 In health, thymus atrophy is okay because T-cells are long lived

T-cell Production Following Bone Marrow Transplantation Depends Upon Thymic Function Bone marrow stem cells Ablative therapies result in a period of T-cell immunodeficiency Individuals are prone to viral infection 0 Age in years 70 Thymic function is a key factor in the production of new T-cells from transplanted bone marrow T-cell production

Thymic Epithelial Stem Cells And Thymus Regeneration Epithelial Stem Cell Compartment Abundant in fetal thymus? Persistence in adult thymus? Cortical Epithelium Medullary Epithelium

Identifying Thymic Epithelial Stem Cells Mts24: a cell surface molecule marking epithelial stem cells? Immunity. 2002 16:803-14. Identification and characterization of thymic epithelial progenitor cells. Nat. Immunol. 2002 3:635-42. Generation of a complete thymic microenvironment by MTS24(+) thymic epithelial cells. Mts24+ Adult thymus

Reconstructing The Thymus Designer thymuses

Thymus of known cellular composition Reconstructing The Thymus

Thymic Reconstitution In Vivo Engineered Thymic Tissue Transplant under kidney capsule of athymic nude mice

T-cell reconstitution following thymus transplantation Grafted Thymus Host Lymph Node Log CD4 Log CD8

Conclusions/References T-cell development relies on contact with thymic stromal cells Manipulating cellular composition of the thymus allows identification of functionally important stromal cell types Seminars in Immunol. 2000 12:457-64. Nature Reviews Immunol. 2001 1:31-40.