Immunology/ Pharmacy Students Lymphopoiesis, T and B cells maturation Lecture 3

1. Immunology/ Pharmacy Students • Lymphopoiesis, T and B cells maturation • Lecture 3 Dr. Mohammad Odibate Department of Microbiology and immunology Faculty of Medicine, Mu’tah University

2. Objectives You should be able to: Identify the sites of B and T lymphocytes production and maturation Describe the structure B and T lymphocytes antigen receptors Understand the process of T cell receptor rearrangement Describe the sequence of B and T lymphocytes maturation Types and functions of different lymphocytes

3. Introduction Hematopoiesis: Is the formation of blood cellular components from the hematopoietic stem cell.

4. Introduction Hematopoiesis

5. T & B lymphocytes Lymphopoiesis Lymphopoiesis is the generation of mature lymphocytes

6. What are the different types of lymphocytes? What are the types of receptors on these lymphocytes? What is the structure of TCRs & BCRs? Why do we have millions of different versions of TCRs? Why do we have millions of different versions of BCRs? Why do we have millions of different versions of MHC molecules? What are requirements for T lymphocytes activation? What are requirements for B lymphocytes activation? What are the steps of T & B maturation in bone and thymus?

7. What are the different types of lymphocytes? T helper lymphocyte T cytotoxic lymphocyte B cell Natural killer cell What are the types of receptors on these lymphocytes? B cell receptor CD4 T cell receptor CD8 T cell receptor Natural killer cell T helper lymphocyte T cytotoxic lymphocyte B cell

8. What is the structure of TCRs& BCRs? Variable region The TCR is composed of two different protein chains (heterodimer). It consists of an alpha (α) and beta (β) chains T lymphocyte Constant region Light chain B cell Heavy chain B cell receptor

9. Why do we have millions of different versions of TCRs? T cell T cell T cell T cell T cell T cell T cell T cell T cell T cell T cell T cell T cell T cell T cell T cell T cell T cell 18 different TCR with each T cell carrying only one version of TCR 18 T-cell

10. Why do we have millions of different versions of TCRs?

11. Why do we have millions of different versions of TCRs? Chromosome 14 V α-genes (70-80) J α-genes (61) C α-gene 1 2 3 4 5 6 ……………….80 1 2 3 4 5 6 ………………….61 Recombinases 3 4 Constant V: Variable J: Joining C: Constant D: Diverse 7 1 Constant Recombinases Chromosome 7 V ß-genes (52) D genes (2) C ß-gene J ß-genes (13)

12. Why do we have millions of different versions of MHC molecules? APC can express a huge number of MHC molecules that eventually react with Antigens in the phagolysosome searching for antigens specific to the MHC binding site APC

13. Activation of T Lymphocytes bacteria Virus MHC 2 MHC 1 Processed Processed Macrophage CD4 T cell receptor CD8 T cell receptor T helper lymphocyte T cytotoxic lymphocyte Activation Activation

14. What are requirements for T cells activation? Prerequisites for Lymphocytes activation CD 4 and CD8 recognizing and binding to MHC class 2 and class 1 respectively TCR should recognize foreign (nonself) antigen complexed with MHC molecules having TCR specific for that antigen

15. Requirements of T lymphocytes activation (nonself) Activation

16. Requirements of T lymphocytes activation 3 MHC1 or MHC2 complexed with foreign antigen CD4 or CD8 Should recognize MHC2 or MHC1 T cell receptor recognizes foreign antigen 2 1

17. Therefore, each lymphocyte recognizes only one specific antigen presented by APC T cell T cell T cell T cell T cell T cell T cell T cell T cell T cell T cell APC

18. What are requirements for B cells activation? Soluble antigen B cell receptor B cell Activation

19. Maturation of B & T lymphocytes The ultimate goal of maturation is to have B and T cells with receptors monospecific for a specific antigen T cell recognizes Only one antigen mature T cell Immature T cell Immature B cell B cell recognizes Only one antigen mature B cell

20. Maturation of B lymphocytes Maturation of B lymphocytes Antigen dependent which takes place in the secondary lymphoid organs Antigen independent which takes place in bone marrow

21. Maturation of B lymphocytes Light chain Heavy chain

22. Maturation of B lymphocytes activation of IgM heavy chain genes The appearance of the IgM heavy chains in the cytoplasm Lymphoid stem cell The appearance of the IgM heavy chains in the cytoplasm 1 Pro-B cell 2 Pre-B cell 3 Late pre-B cell 4 theappearance of IgM on the surface Immature-B cell 5 theappearance of IgD on the surface Mature-B cell 6

23. Maturation of B lymphocytes Before leaving the bone marrow the mature B cells undergo apoptosis if they recognized self antigens offered by antigen presenting cells Dendritic cell Self antigen Mature-B cell Apoptosis antigen independent maturation Recognized self antigen

24. Maturation of B lymphocytes Each B cell leaving bone marrow to the secondary lymphoid organs displaying specific IgM (BCR) for a specific antigen Mature B cells leave bone marrow to the secondary lymphoid organs

25. Maturation of B lymphocytes Antigen dependent B cell maturation: occurs in the secondary lymphoid organs

26. Maturation of T lymphocytes Recognized MHC Nursing cell MHC1 MHC2 In thymus positive selection CD4 TCR Nursing cell offers MHC1 & 2. Cells that recognize either MHC1 or MHC2 will survive (positive selection) Lymphoid stem cell CD8 Apoptosis (Double negative CD4- & CD8-) (TCR-) (Double positive CD4+ & CD8+) (TCR+) Did not recognize MHC

27. TCR+ CD4+ T Helper cells (TH) CD4 engaged at first with MHC2 CD8 engaged at first with MHC1 The next step is to have T cells with either CD4 or CD8 but not both TCR+ CD8+ T cytotoxic cells (Tc)

28. self antigen APC offer MHC 2 complexed with self antigens APC Did not recognize self antigen (survive) TH TH Recognized self antigen. It will undergo apoptosis TH TH Cells will undergo a second challenge called negative selection. Negative selection Tc Recognized self antigen. Tc Tc Tc Did not recognize self antigen (survive) APC offer MHC 1 complexed with self antigens APC

29. Maturation of B lymphocytes TH TCR+ CD4+ T Helper cells (TH) Recognized MHC2 (positive selection) Did not recognize self antigens (negative selection) Tc TCR+ CD8+ T cytotoxic cells (Tc) Recognized MHC1 (positive selection) Did not recognize self antigens (negative selection)

30. Lymphocytes Typically, lymphocyte is small, round, cell with diameter of 5-10μm, spherical nucleus, and scanty cytoplasm Resting lymphocytes are known as naïve cells Different lymphocytes are identified by certain protein markers on their surface called "cluster of differentiation" or "CD" system. There are three major types of lymphocyte, B lymphocyte, T lymphocyte and NK cells.

31. Lymphocytes • B Lymphocytes • In humans the development and maturation of these cells occur in bone marrow • B cells differentiate into antibody producing plasma cells • Plasma cells: • Plasma cells are oval or egg shaped, have eccentrically placed nuclei • These are the effector cells of the B-cells and are specialized in secreting immunoglobulins • When activated B cells divide, some of its progeny become memory cells (survive 20 years or more) and the reminders become immunoglobulin-secreting plasma cells. • They have a short life span of few days to few weeks.

32. Thank you