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Chapter 5

Chapter 5. Understand how the thymus is the site of development for T cells How do cells commit to a lineage during T cell development How do we eliminate self-reactive T cells without eliminating the ability to recognize self-MHC. The Development of T Lymphocytes. Two types of TCR

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Chapter 5

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  1. Chapter 5 • Understand how the thymus is the site of development for T cells • How do cells commit to a lineage during T cell development • How do we eliminate self-reactive T cells without eliminating the ability to recognize self-MHC

  2. The Development of T Lymphocytes Two types of TCR 1. αβ T cells CD4 CD8 2. γδ T cells

  3. T cells develop in the thymus T cells (T-lymphocytes) = thymus-dependent lymphocytes The thymus is a primary lymphoid organ because it is only involved in development, not fighting infection. The thymus contains a) Thymocytes (immature T cells) b) Thymic stroma (epithelial cells)

  4. The Thymus 2 areas of the thymus: Cortex – outer, close-packed consists of ectodermal cells; can contain thymocytes and macrophages Medulla – inner, less dense consists of endodermal cells; contains thymocytes, dendritic cells, and macrophages Thymic anlage : The combination of the ectodermal and endodermal cells, colonized by progenitor cells from the bone marrow.

  5. Thymus facts • Fully developed at birth and increases in size until puberty • Most active in the young • Degrades after puberty (involution), being replaced with fat tissue • Even after involution (~30 yrs. old) or a thymectomy immunity by T cells is not impaired significantly • Mature T cell repertoire is long-lived and self-renewing

  6. T cell markers T Cell receptor – αβ or γδ chains bind peptide antigens CD3 – complexes of CD3γε, CD3δε, and 2 ζ chains for signaling to the interior of the cell CD4 or CD8 – receptors that bind MHC molecules Progenitor cells entering the thymus have NO TCR, CD3, or CD4/CD8 surface receptors = immature thymocytes called double-negative thymocytes After β chain rearrangement, T cells express both CD4 and CD8 surface receptors = immature thymocytes called double-positive thymocytes Mature T cells express either CD4 or CD8 surface receptors = thymocytes called single-positive thymocytes

  7. TCR gene rearrangement Order of TCR gene rearrangements controls the distribution of T cell lineages: 95% αβ T cells 5% γδ T cells

  8. T cell lineages Pre T cell  (pT) - a place-holder

  9. αβ TCR rearrangement • β chain • rearranges first • has variable (V), diversity (D), and joining (J) gene segments • Can attempt gene rearrangements on both chromosomes or by a second rearrangement on the same chromosome • Tandem DJ and V segments • 80% of T cells make successful rearrangements • Successful rearrangement leads to expression of CD4 and CD8 • α chain • rearranges second • has several variable (V) and joining (J) gene segments • Can undergo several gene rearrangements • Both α chain loci can rearrange leading to the potential for 2 different α chains and 2 different TCRs on a single cell

  10. Gene rearrangement . . . In pictures

  11. β chain rearrangement

  12. α chain rearrangement

  13. γδ T cells • Express rearranged TCR’s, generate immunologic memory and induce dendritic cell maturation • Effector functions similar to  T cells making them part of the Adaptive immune system • HOWEVER, they have limitied TCR gene usage, TCRs act as pattern recognition receptors, and respond fast • Might be a conserved, primitive form of immunity that bridges INNATE with ADAPTIVE

  14. Proposed scheme to use  T cells for immunotherapy

  15. T cell generation in mice The first γδ T cells express receptors based on the first V segment nearest the D segments (epidermis- yellow). Later the majority of γδ T cells express receptors with the other V segment (reproductive tract - red). After birth the αβ T cells dominate.

  16. Positive and Negative Selection of T Cells Where: cortex, cortico-medullary junction (thymus) Who: double positive, a:b T cells What is being selected: the TCR • Purpose • Positive Selection: Select TCRs that recognize self MHCs • -In periphery, T cells recognize foreign peptide that is presented by self MHCs • -T cells must recognize (bind to) self MHCs to be activated by • foreign peptide • Negative Selection: EliminateTCRs that recognize self • -T cells recognizing self MHC containing self peptides are • potentially autoreactive

  17. Positive Selection (PS) • TCR physically binds to MHC on APC • Select T cells that can recognize self MHCs • Primary thymic repertoire has bias toward general MHCs • -select those TCR that recognize inherited self MHCs • (6 MHC I and minimally 6 MHC II) • Only 2 % of a given thymic repertoire can recognize self • MHCs; PS: process of stimulation those T cell to mature POINT: Thymic T cells undergoing positive selection are pre-programmed to die unless they receive a signal to live and mature (98% DIE) • How are thymocytes (T cells in the thymus) positively selected? • thymic cortical epithelial cells express MHC I and MHC II on their surface • MHC molecules not stable in absence of peptide; all contain self peptides • a:b chains of TCR test all MHC complexes for ones they recognize (bind to) • -if bound with 3-4 days: signal to live; if not, DIE by default • -120,000 self peptides presented by 12 different MHC molecules; most involved • in positive selection

  18. Bone Marrow Transplant: Share HLA Allotypes • Bone marrow transplant: destroy • recipient bone marrow cells including • hematopoietic stem cells • Reconstitute all blood cells including • lymphocytes with donor cells • T cells selected on self (recipient) • MHC (thymus) • APCs developing in bone marrow are • donor • Recipient T cells can not recognize • donor APCs, unless donor and • recipient have some common (share) HLA (MHC) molecules • Minimum: share one common MCH I molecule and one common MHC II molecule

  19. Transition from Double Positive to Single Positive • Choice of whether to become a CD4+ T cell • or CD8+ T cell is determined during • positive selection • Single positive T cells: express either CD4 • or CD8, but NOT both • Developing T cell interacts with MHC I on • thymic stromal epithelial cells: CD8+ • Developing T cell interacts with MHC II on • thymic epithelial cells: CD4+ • Bare lymphocyte syndromes • -patients lacking MHC I have only CD4+ • cells • -patients lacking MHC II have only CD8+ • cells

  20. a Chain Gene Rearrangement During Positive Selection • a chains of the TCR can continue to rearrange to enhance chances of passing • positive selection (reminiscent of light chain rearrangement: BCR) • Permits development of • single T cell with two • different a chains • Probability of both chains • passing positive selection • is extremely remote • Result: only one functional • TCR per T cell

  21. Negative Selection • Select cells for elimination that express • TCRs that strongly recognize self MHC • presenting self peptides Where: cortico-medullary junction Who is selecting: macrophages and dendritic cells How: strong binding of the TCR sends signal to DIE (apoptosis) Two individuals of completely different haplotypes have non-overlapping T cell repertoires: the T cell repertoire is highly personalized.

  22. Mature, Naïve T Cells Meet Ag in Secondary Lymphoid Tissue • Only 1-2% of immature T cells survive selection in the thymus • Surviving cells leave, enter the periphery and circulate through secondary • lymphoid tissue • Naïve T cells are long lived and can circulate for years in the absence of • Ag (antigen) • Meet Ag in the T cell area of the secondary lymphoid tissue Ag stimulates naïve T cells Effector T cells CD8+ Cytotoxic T cells CD4+ Helper T cells CD4+ Helper T cells TH1 TH2 Thymus: Leave Leave Stay • Twice as many CD4+ T cells in the circulation than CD8+ T cells

  23. Alloreactive T Cells • 5-10% of T cell repertoire reacts strongly to allogenic • cells (non-self MHC) • Allograft rejection (kidney) • T cell repertoire biased to recognize MHC molecules in • general • Elimination of those T cells that recognize self MHCs • (negative selection) leaves an increased proportion of • T cells recognizing non-self MHC (allogenic)

  24. 12 Different MHC Isotypes is Optimal • Double MHC isotype number; double those passing • positive selection • Double number of isotype number; geometrically • increase those deleted by negative selection • Too many MHC isotypes will significantly limit the T • cell repertoire • 12 isotypes appear optimal Note: Skip Fig. 5.15

  25. Development of T Cell Tumors T cell tumors represent different stages of T cell development (like B cell tumors)

  26. T Cell Development in the Thymus

  27. Stages of a:b T Cell Development

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