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- 2. Topics we will understand today ◦ Early Development ◦ Repertoire selection Processes ◦ Late Development ◦ Activation ◦ Differentiation ◦ Cell Death 2
- 3. I AM RASHMI PhD Student, Allergy and Immunology Unit, Dept.of Pediatrics, PGIMER, Chandigarh 3 ‘All T cells show adaptive immune response’
- 4. Immune response 4 ◦ Gamma delta T cells may be considered a component of adaptive immunity in that they rearrange TCR genes to produce junctional diversity and can develop a memory phenotype ◦ Activated NKT cells produce several cytokines with the capacity to jump-start and modulate an adaptive immune response
- 5. Importance of adaptive immune response ◦ Innate immune response can plateau the pathogenic infection. ◦ However, complete clearance requires adaptive immune response 5
- 6. T cell development and activation 6 T-cell precursor rearranges its T- cell receptor genes in the thymus Immature T cells that recognize self MHC receive signals for survival. Those that interact strongly with self antigen are removed from the repertoire Mature T cells encounter foreign antigens in the peripheral lymphoid organs and are activated Activated T cells proliferate and eliminate infection T-cell progenitors develop in the bone marrow and migrate to thymus Positive and negative selection in the thymus Matute T cells migrate to the peripheral lymphoid organs Activated T cells migrate to sites of infection
- 8. T cell precursor migration from Bone marrow to thymus 8 1o lymphoid organ 1o lymphoid organ Chemo attractants: Thymosin Thymotaxin Thymopoietin Thymic factors T cell precursor
- 9. Each of the several million T and B cells circulating in the body expresses a novel and unique antigen receptor ○Cells entering the thymus are not yet committed to become a lymphocyte and express no antigen-specific receptors ○Cells leaving the thymus are functional and express unique TCRs 9 T cell development
- 10. T cell commitment ◦ Progenitor T cells migrate from bone marrow to thymus ◦ T cells can be grown in vitro in absence of thymic fragments ▫ Grown on bone marrow stem cells with Notch protein (transcription factor) ■ Notch protein is key in determining T-lineage specification 10
- 11. T cell development Vertebrates generate 2 broad categories of T cells: 11 ○TCR-αβ – dominant participant in adaptive immune response ○TCR-γδ – protect barrier tissues from outside infection -First cells to arise during fetal development, drop off after
- 12. T cell development Begins with arrival of small numbers of lymphoid precursors migrating from blood to thymus ○When they do arrive in thymus, T-cell precursors don’t express signature surface markers (CD3, CD4, and CD8) ○Do not yet express RAG-1 or RAG-2 that are necessary for gene rearrangement 12
- 13. 13 Thymic cells Thymosin Thymotaxin Thymopoietin Thymic factors RAG1 & RAG2 CD4 CD8 TCR Various TCR gene rearrangements takes place at this point MHC II MHC I + selection - selection Thymocytes failing to recognize both MHC molecules through respective CDs, undergo APOPTOSIS FAS FAS L Self-antigen Thymocytes recognizing self antigen with high affinity undergo APOPTOSIS Stronger signal between these two decides the fate of Single positive cell
- 14. Let’s just revise what we have learnt till now!! ◦ Progenitor T cells migrate to thymus ▫ At about 8th or 9th week of gestation in humans ◦ T cell maturation involves rearrangements of the germ-line TCR genes ◦ In thymus, thymocytes proliferate and differentiate ▫ Early Thymocyte Development ▫ Positive and Negative Selection ▫ Lineage Commitment 14
- 15. 15
- 16. WANT BIG IMPACT? Use big image. 16
- 17. 17
- 18. You have Fluorescein-labeled anti-CD4 and phycoerythrin- labeled anti-CD8. You use these antibodies to stain thymocytes and lymph- node cells from normal mice and from RAG-1 knockout mice. In the forms below, draw the FACS plots that you would expect. 18
- 19. 19
- 20. WANT BIG IMPACT? Use big image. 20 Start expressing CCR7
- 21. Abnormal genes reported in SCID patients 21
- 22. 22
- 23. 23
- 24. Selection process in thymus Positive selection ○Survival of only T cells whose TCRs recognize self-MHC molecules ○Ensure MHC restriction — Negative selection ○Eliminates T cells that react too strongly with self MHC or MHC with self-peptides 24
- 25. Thymocytes “learn” MHC restriction in thymus ž 25 • Selection process results in development of T cells that might respond to certain MHC molecules • This prevents supernumerary wandering lymphocyte generation and also ‘economical’
- 26. Death by neglect ž T cell development is expensive for host ○98% of all thymocytes do not mature, die by apoptosis within thymus ○However, the benefits of having functional T cells outweigh the costs 26
- 27. Positive selection ensures MHC restriction ž 27
- 28. Failure of Apoptosis causes defective lymphocyte homeostasis 28 FAS knockout mice Normal mice
- 29. Separate pathways for intracellular and extracellular ‘self’ molecule 29
- 30. Do we delete Thymocytes reactive to tissue-specific antigen? Thymus has an extraordinary capacity to express and present proteins from all over the body. Medullary epithelial cells express a unique protein, AIRE (Autoimmune regulator), that allows cells to express, process, and present proteins that are ordinarily only found in specific organs. AIRE is part of transcriptional complex that facilitates expression of tissue-specific genes by regulating not only translation, but also chromatin packing 30 Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome Thymus: Cosmopolitan city of body
- 31. 31 Deletion of auto-reactive TCR
- 32. What stages of T-cell development (DN1, DN2, DN3, DN4, DP, CD4 SP, or CD8 SP) would be affected in mice with the following genetic modifications? Justify your answers. a. Mice that do not express MHC Class II. b. Mice that do not express AIRE. c. Mice that do not express the TCR-alpha chain. 32
- 33. Exit from thymus and final maturation ž ž Mature T cells that survive the selection process leave the thymus ○Recent thymic emigrants RTE are not as functionally mature as most naïve T cells in the periphery: they do not proliferate or secrete cytokines as vigorously in response to T-cell receptor stimulation. 33
- 34. Treg Cells ◦ Shown to inhibit proliferation of other T cells in vitro CD4+CD25+ ◦ Shown to inhibit development of autoimmune diseases 34
- 35. Treg cells 35
- 36. Cell Death and T cell populations Apoptosis plays critical role ◦ — Deletion of potentially autoreactive thymocytes ◦ — Deletion of T cell populations after activation ◦ Fas and FasL pathway to induce self death 36
- 37. 37
- 38. 38
- 39. Fas or Fas-L deficiency CD3+ cells in periphery 39 Control Canale-Smith syndrome patient
- 40. T cell activation and diffrentiation 1 40
- 41. ◦ Role of APCs ◦ Signal 1, 2 and 3 ◦ Co-inhibitory pathway ◦ Immunological exhaustion 41
- 42. 42 T cell – APC interaction © The copyright for this work resides with the British Society for Immunology
- 43. Signaling molecules and space 43 supramolecular activation complexes
- 44. Signaling molecules and space 44
- 45. APC migration and specific activation 45
- 47. 47 Signal 1, 2 and 3 o Antigen receptor binding and Co-stimulation IL-6, IL-12, TGF-β, IL4
- 48. 48
- 49. 49 Differences in the properties of professional antigen-presenting cells that induce T cell activation
- 50. 50 Pathways influenced with PHA, PMA and ionomycin
- 52. 52
- 53. 53
- 54. 54 Anergy Lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance
- 55. Anergy 55
- 56. Q/A ◦ Which of the following conditions would lead to T- cell anergy? ▫ A naïve T-cell interaction with a dendritic cell in the presence of CTLA-4 Ig. ▫ A naïve T cell stimulated with antibodies that bind both the TCR and CD28. ▫ A naïve T cell stimulated with antibodies that bind only the TCR. ▫ A naïve T cell stimulated with antibodies that bind only CD28. 56
- 57. 57 Antigen Co-stimulation No co-stimulation Infectious agent Protective immunity Recurrent infection Innocuous substance Allergy No Allergy Grafted organ Rejection Acceptance Self organ Autoimmunity Self tolerance Tumor Tumor immunity Cancer Regulation of Co-stimulation is critical
- 58. 58 Cell surface signaling molecules in control of immune response
- 60. 60 • Your lab acquires mice that do not have the GATA-3 gene (GATA-3 knockout mice). You discover that this mouse has a di cult time clearing helminth (worm) infections. Why might this be? Q/A
- 61. 61
- 65. Immunological Exhaustion ◦ Loss of CD8 T cell function ◦ Occurs with chronic infection or cancer ◦ CD8 T cell exhaustion correlates with higher antigen, duration of infection, loss of CD4 help ◦ Blockade of inhibitory receptors can rescue CD8 T cells 65
- 66. Role of CD4+ helper Tcells 66
- 67. Exhaustion 67
- 68. Poly 68
- 69. Conclusion ◦ Early Development ◦ Repertoire selection Processes ◦ Late Development ◦ Activation ◦ Differentiation ◦ Cell Death 69
Notes de l'éditeur
- Transporter associated with antigen processing (TAP) protein complex belongs to the ATP-binding-cassette transporter family
- C-kit- receptor for stem cell growth factor CD44-adhesion molecule CD25- alpha chain of IL-2 Receptor
- CCR7 directs t cells to lymph nodes
- Assembly of this complex results in intracellular signals that induce a variety of processes, including the maturation to the DP stage
- cortical thymic epithelial cells
- Central tolerance
- HEV specialized post-capillary venous swellings characterized by plump endothelial cells as opposed to the usual thinner endothelial cells found in regular venules. Present in all secondary lymphoid organs This tight binding stops further movement of the T cell which can then move between HEV cells into the lymph node by a process termed 'diapedesis’
- Grail: Gene related to Anergy in lymphocytes Cbl: negatively regulated activation signals; defect in cbl display lower activation threshold in patients
- Clonal anergy: low-affinity ligand in the presence of costimulation Tr1: subset of adaptive CD4+ T cells that promote immune tolerance and control excessive and/or inappropriate inflammation mediated by effector T cells and APCs CD25: Also expressed by myeloid dendritic cells Adaptive immune tolerance: Raised against Stress; Liver usually remains in relatively immune-compromised because it has to process many things T-T: The unresponsive state induced (T-T Cell presentation in Table 1) had clonal anergy properties in that IL-2 production was inhibited, the state persisted in the absence of antigen, and it was reversible upon stimulation with IL-2.
- Can talk about adverse effects of overstimulation like MAS.