Introduction to Immunology Part 2 September 30, Dan Stetson

Transcription

1 Introduction to Immunology Part 2 September 30, 2016 Dan Stetson stetson@uw.edu 441 Lecture #2 Slide 1 of 26

2 CLASS ANNOUNCEMENT PLEASE NO TREE NUTS IN CLASS!!! (Peanuts, walnuts, almonds, cashews, etc) Serious (life-threatening) food allergies*** ***Note: by the end of this quarter you ll know how allergies work 441 Lecture #2 Slide 2 of 26

3 Two introductory lectures: Broad Overview (You ll hear all of this again in more detail) Part 1 (Wednesday): Course overview History of and perspectives on Immunology Cell types of the immune system Initiation of immune responses Part 2 (Today): T and B cell responses Anatomy of the immune system Effector mechanisms and immune memory 441 Lecture #2 Slide 3 of 26

4 Some Innate Immune Cells Show Captured Antigen to Adaptive Immune Cells: Antigen Presentation: the link to adaptive immunity These cells are called Professional Antigen-Presenting cells (APCs) Major activator of adaptive immunity 441 Lecture #2 Slide 4 of 26

5 Which cells respond to antigen? Adaptive Immune Cells 441 Lecture #2 Slide 5 of 26

6 Adaptive Immune Cells Two types of lymphocytes: B cells and T cells Both express very specific receptors that usually recognize only one piece of one pathogen. B cells recognize soluble antigen. T cells recognize pieces of antigen presented on the surface of another cell. These cells mediate the nearly limitless specificity of immune responses. 441 Lecture #2 Slide 6 of 26

7 How can the immune system make antibodies to anything? The Clonal Selection Theory Frank McFarlane Burnet (~1955) There must be many cells in the body, each expressing a unique antibody receptor on its surface specific for a single determinant: One cell, one antibody (Proven by G. Nossal and J Lederberg 1958) Once a particular cell is triggered by the determinant, the cell divides a lot and secretes the antibody receptor. Clonal expansion and selection This was all proposed before lymphocytes were even identified and characterized! 441 Lecture #2 Slide 7 of 26

8 What do lymphocyte receptors look like? B Cells: Antibodies, Immunoglobulins, B Cell Receptors (BCRs) T Cells: T Cell Receptors (TCRs) B cell receptors (antibodies/immunoglobulins) were studied first because antibodies could be purified from serum and analyzed biochemically. Can be membrane-bound OR secreted Membrane-bound ONLY 441 Lecture #2 Slide 8 of 26

9 How is diversity generated within BCRs and TCRs? V gene segments D J Constant region RNA V region C region Protein Somatic rearrangement of gene fragments generates combinatorial diversity Lymphocytes are the ONLY cells in the body that do this (the genome of each lymphocyte is different from that of every other cell in the body) The individual V, D and J gene segments are randomly joined together There is RANDOM chance of generating self-reactive, foreign-reactive, or completely nonreactive specificities 441 Lecture #2 Slide 9 of 26

10 How does the immune system censor self-reactive lymphocytes? The Goldilocks Principle Cells with a bad receptor die by neglect Cells that have a functional receptor are selected for further development: positive selection Cells that are strongly self-reactive are purged from the repertoire: negative selection The mature pool of lymphocyte clones contains cells that are just right **It is impossible to purge ALL self-reactivity from the repertoire since autoimmunity exists. Other mechanisms are in place to regulate this. 441 Lecture #2 Slide 10 of 26

11 Lymphoctyes Require Two Signals for productive activation Coincidence detection ensures responses only under the right conditions Signal 1 Self An1gens APC T cell Anergy (Unresponsiveness) Signal 1 APC T cell Ac1va1on Pathogens Signal 2 Signal 2 is under the control of the innate immune system 441 Lecture #2 Slide 11 of 26

12 T Cells Recognize Fragments of Pathogens That Are Presented On The Cell Surface By Major Histocompatiability Molecules (MHC) Microbe T Cell TCR MHC Professional APC (DC) Two types of MHC molecules: MHC Class I and MHC Class II MHC Class I molecules are expressed by nearly all cells in the body MHC Class II molecules are more restricted: dendritic cells, macrophages, B cells Helper T cells (CD4 T cells) detect peptides in MHC Class II Cytotoxic T cells (CD8 T cells) detect peptides in MHC Class I 441 Lecture #2 Slide 12 of 26

13 Phagocytosed Antigen Presented By MHC Class II Activates Helper T Cells Via Interaction with CD4 on the T cell Microbe T Helper Cell TCR MHC Class II CD4 Professional APC (Dendritic Cell) T cell help T H cells secrete soluble factors (cytokines) that orchestrate the immune response by recruiting and activating other types of cells 441 Lecture #2 Slide 13 of 26

14 Peptides synthesized within the cell (ie during viral infection) are presented By MHC Class I Molecules Peptide/MHC Class I activates cytotoxic T cells through TCR and the CD8 molecule T Cell TCR CD8 MHC MHC Class I APC CD8 + Cytotoxic T cells usually kill the cell that is showing them the antigen 441 Lecture #2 Slide 14 of 26

15 B Cells Produce The Antibodies Found in Serum B Cell Soluble antigen BCR (Ig, Antibody) Antigen determinant 441 Lecture #2 Slide 15 of 26

16 Activated B Cells Become Plasma Cells That Secrete Lots of Antibody Specific signals drive a B cell to switch its antibody from a membrane-bound To a secreted form Plasma cells can secrete enormous amounts of antibody: ~3,000 antibodies per second per cell 441 Lecture #2 Slide 16 of 26

17 The Link between T and B Cells B cells express MHC Class II: they are also APCs Unlike DCs, B cell APC function is largely restricted to the specific antigen recognized by the BCR B Cell B Cell B Cell MHC Class II B Cell B Cell T Cell T cell help Plasma Cell These antibodies are called T-dependent 441 Lecture #2 Slide 17 of 26

18 Following T/B Interaction, activated B Cells Form Germinal Centers Where the BCRs Mutate to Fit Antigen Better Mutations V region C region Rearranged DNA B cells whose mutated V regions fit the antigen better outcompete other B cells and proliferate more: Affinity Maturation B cells are the only cells in the body that do this This process is carefully regulated to prevent autoreactivity and cancer 441 Lecture #2 Slide 18 of 26

19 Memory T cells and B Cells respond faster and more vigorously upon encountering antigen the second time The goal of vaccines is to generate immune memory before infection 441 Lecture #2 Slide 19 of 26

20 Where to immune cells come from? Where are they going? Primary lymphoid organs: Most lymphocytes develop in these B cells: Bone marrow T cells: Thymus Secondary lymphoid organs: sites where mature T and B cells reside, antigen filters in or is brought in by DCs and adaptive immune responses are initiated. Lymph Nodes, Spleen, Peyer s Patches (small intestine) 441 Lecture #2 Slide 20 of 26

21 Lymphocytes move through blood and lymph Lymph: Interstitial Fluid Extracted From Blood By Filtration Across Capillary Endothelium Artery Arteriole Capillary High Pressure Fluid seeping from capillary = Lymph Lymphatic vessels are just as numerous as blood vessels! 441 Lecture #2 Slide 21 of 26

22 Circulation Patterns of Naïve Lymphocytes Naïve lymphocytes migrate from the blood into a lymph node (using special homing molecules) They then traffic through the lymphatic vessels from lymph node to lymph node until they re-enter the blood via the thoracic duct. This pattern is repeated over and over, unless the lymphocyte is activated. 441 Lecture #2 Slide 22 of 26

23 The Efficiency of Lymphoid Anatomy Dendritic Cells Bring Antigen from Tissue To The Nearest ( Draining ) Lymph Node This concentrates all activated DCs and antigens in a central place to be sampled by naïve lymphocytes 441 Lecture #2 Slide 23 of 26

24 441 Lecture #2 Slide 24 of 26

25 The Spleen Collects Lymphocytes and Antigen from the Blood Rather Than Lymph Red Pulp White Pulp Old red blood cells are also removed in the spleen 441 Lecture #2 Slide 25 of 26

26 Summary: Part 2 Adaptive immune system: T and B cells Somatic gene rearrangements generate enormous receptor diversity The mature pool of lymphocytes is largely purged of self-reactivity Lymphocytes detect different forms of antigen: B cells: soluble antigen Helper T cells: peptides presented in MHC Class II Cytotoxic T cells: peptides presented in MHC Class I The anatomy of lymphoid organs allows rare cells to find each other and facilitates activation of naïve T and B cells 441 Lecture #2 Slide 26 of 26