MICR 304 Immunology & Serology

1. MICR 304 Immunology & Serology Lecture 11 T Ly Chapter 6.8,6.10,6.11,6.19,7.7-7.10, 7.13-7.22, 7.26, 7.29,8.4, 8.11-8.33 Fig. 6.18

2. Overview of Today’s Lecture • Cell signaling through TCR • Development of T cells • Positive and negative selection • Survival and maturation in peripheral lymphoid tissue

3. Key Players in Immunology

4. T-Lymphocyte Characteristics • Originate in bone marrow • Migrate to and mature in thymus (thymocyte) • Differentiation is mediated through NOTCH1 receptor • Antigen recognition through T-cell receptor • Recognize digested antigen • Recognize antigen presented on specialized molecules called MHC I and II Most T cells

5. T Cell Receptor Complex • TCR: antigen –recognition proteins • CD3, z: invariant signaling proteins containing ITAM motif

6. Activation of T Cell Receptor • Not clear yet • Dimerizing of TCR? • Conformation change of TCR • Clustering of T cell co-receptor and CD4? • Formation of immunological synapse

7. Immunological Synapse • Structure formed around the site of contact between a T cell and its antigen presenting cell • TCR, co-receptor, and signaling proteins concentrated at the contact site • Two zones • Central supramolecular activation complex (cSMAC) • Signaling proteins • CD28: costimulatory • CD2: adhesion molecule • Peripheral supramolecular activation complex (pSMAC) • LFA-1: Integrin • Talin: cytoskeletal protein

8. Kiss of Death Immunological synapse also plays a role in secretion of cytokines and cytotoxic granules.

9. T Cell Activation through TCR • Fyn and Lck phosphorylate ITAMS in T cell receptor complex allowing Fyn to bind ZAP-70. • Subsequent signaling is similar to B cell signaling.

10. CD 28: Co-Stimulatory Receptor for Naïve T Cells • Important for stimulation of naïve T cells • CD28expressed on naïve T cells • Binds to the co-stimulatory ligands B7.1 (same as CD80) and B7.2 (same as CD86). • Expressed on specialized APC like dendritic cells.

11. Simultaneous Activation of TCR and Co-stimulatory Molecules is required for T Cell Effector Response

12. Activated T Cells Secrete and Respond to IL-2

13. MHC Molecule Participates in Antigen Recognition • Co-recognition of foreign peptides and MHC molecule • Resulting from direct contact between TCR and MHC • Indirect effect of MHC polymorphism on the peptides that bind to MHC or on their bound conformation

14. Alloreactivity of T Cells Normal Antigen fits well to TCR Allogeneic MHC molecules fits well to TCR

15. T Cell Development

16. Main Phases of a T Cell’s Life History

17. Main Steps in T Cell Development

18. The Thymus • Organ in upper anterior thorax above heart • Consists of numerous lobules • Outer cortex • Inner Medulla • Main cell types • Network of epithelial cells (thymic stroma) • Developing T-Cells • Macrophages, dendritic cells • Is developed at birth, greatest T-cell production by puberty, then slow regression • In mice secondary thymus-like tissue found in neck

19. How do we Know that T-cells are Important in Immunity? • Studies with mice • Thymectomy at birth leads to immunodeficiency • Nude mice • Gene defect: no thymus, immunodeficient and hairless • Human disease: DiGeorge’s Syndrome • Lack of thymus associated with immunodeficiency

20. Cellular Organization of the Thymus Bone marrow precursor Immature T-Cells 95% die Mature naive T-Cells Hassall’s corpuscle (Cell destruction?) Blood stream

21. Interaction of Thymocytes with Epithelial Cells in Thymus Thymocyte Epithelial Cell

22. Removal of Dysfunctional Thymocytes • Takes place mostly in thymic cortex • Thymocytes undergo apoptosis • Failure to interact with self MHC molecules • Strong response to self peptides • Apoptotic cells (red stain) are rapidly phagocytosed by macrophages (blue stain)

23. Marked Changes of Cell Surface Markers in Developing Thymocytes Positive/Negative Selection

24. CD4 and CD8 Expression in Developing T Cells

25. Positive and Negative Selection of Thymocytes • Double positive thymocytes have a life span of 3 to 4 days and are programmed to enter apoptosis if not rescued. • Developing thymocytes are exposed to self peptide presented on self MHC molecules • They are rescued from apoptosis if their TCR recognizes self-peptide on self MHC molecules. • However, if their TCR responds too strongly to self peptide on self MHC molecules, they are sent to apoptosis.

26. Tissue Specific Protein Expression in the Thymus • Specialized stromal cells in the thymic medulla express so called tissue specific proteins. • The expression of such genes is controlled by AIRE (autoimmune regulator) Green: AIRE Red: thymic medullary epithelial marker

27. Effector T Cells

28. Effector T Cells

29. The Various Effector T cells and Their Role in Host Defense Activate epithelial cells

30. Effector Molecules ofActivated Effector Cells Cytotoxicity Macrophage enhancement Allergy Neutrophil recruitment Epithelial cell activation Down regulation of immune response

31. Well Defined T Cell Derived Cytokine (1)

32. Well Defined T Cell Derived Cytokine (2)

33. Activation of Naïve T Cells by Dendritic Cells

34. Refresher: Antigen Presenting Cells

35. APC Derived Cytokines Influence the Differentiation of TH Cells

36. Differentiation of TH Cells

37. Today’s Take Home Message/Active Learning Exercise • Complete the figure by adding all relevant cytokines including signal 3.