BMS 545 Immunology - NK Cells & Adaptive Overview (PDF)

WELCOME! BMS 545 IMMUNOLOGY SEPTEMBER 16, 2024 ANNOUNCEMENTS  Office Hours  Tuesday 4-5 pm (virtual)  Thursday 4-5 pm (316J)  DITKI due Wednesday by 12:59 pm  Adaptive Immunity- Cellular WITH QUIZ  RE-VIEW Thymus, Spleen, & Lymph Nodes (NO QUIZ) WHY SHOULD YOU CARE?...

WELCOME! BMS 545 IMMUNOLOGY SEPTEMBER 16, 2024 ANNOUNCEMENTS  Office Hours  Tuesday 4-5 pm (virtual)  Thursday 4-5 pm (316J)  DITKI due Wednesday by 12:59 pm  Adaptive Immunity- Cellular WITH QUIZ  RE-VIEW Thymus, Spleen, & Lymph Nodes (NO QUIZ) WHY SHOULD YOU CARE?  https://www.healio.com/news/h ematology- oncology/20220119/fda-grants- fast-track-designation-to- natural-killer-cell-therapy-for- gi-cancers  OBJECTIVES  State where you would expect to find receptors of the adaptive immune system within the context of the cell and correlate the ligands and receptors of the two types of immune cells with their signaling outcomes (more on this later too, but today it’s KIR & KAR)  Compare and contrast NK & NKT cells  Describe how NK cells can work with macrophages & dendritic cells to bring about an immune response  Outline the movement of lymphocytes throughout the body and key anatomical features  Describe how adaptive immune system differs from innate & unique features of the adaptive immune system  Recognize & describe the microenvironments where adaptive immune cells mature & the adaptive immune response develops  Identify the primary & secondary immune organs in vertebrates & describe their function in relation to the adaptive immune system  REFRESHER: INTERFERON RESPONSE TO INTRACELLULAR MICROBIAL INVASION  Interferon- family of cytokines that act specifically to induce cells to resist viral infections  Rapidly produced when viral PAMPs interact with PRRs  Main interferons are IFN-α & IFN-β (type 1 interferons) and produced by a variety of cells  Induce cells to activate antiviral defenses like RNA-dependent protein kinase pathway & apoptotic (programmed cell death) pathway  IFN-γ (type II interferon)- structurally & functionally unrelated to type I interferons, but produced by activated lymphocytes like CD4 T cells, CD8 T Cells, NK Cells, & ILCs.  Acts principally to activate macrophages in both innate and adaptive immunity Don’t mix-up Type I interferons with Type 1 immunity Type 1 immunity protects against intracellular microbes through activation of mononuclear phagocytes; mediate autoimmune INTERFERON RESPONSE TO INTRACELLULAR MICROBIAL INVASION  Inflammation, innate immunity, and lymphoid cells 3-20 NK cells are circulating lymphocytes of the innate immune response & provide an early response to viral infections Figure 3.44 NK cells circulate between blood and tissues HEV = high endothelial venule  NK & NKT CELLS True NK cell on left, NKT on right  Kill certain virally infected cells & tumor cells without prior sensitization such as:  some virus-infected cells  cells covered with antibody  cells that do not express normal levels of class I MHC  Play a role in both innate AND adaptive even though they are descended from CLP  Similar to Innate Lymphoid Cells (ILCs) & Lymphoid tissue inducer (LTi)  Lymphoid cells that function in innate immune system  (*NEW*) Natural Killer T cell (NKT)- a unique subset of T cells develop within thymus & express a rearranged TCR of extremely limited repertoire  Unlike T cells, NKT respond to lipids, glycolipids, or hydrophobic peptides presented by a specialized, nonclassical MHC class I molecule (CD1d), & secrete large amounts of cytokines, especially IL-4  Inflammation, innate immunity, and lymphoid cells 3-22 NK-cell cytotoxicity is activated at sites of virus infection Activation by type I interferon induces NK-cell proliferation & differentiation into cytotoxic effector cells KILLER ACTIVATION RECEPTORS & KILLER INHIBITION RECEPTORS  NK cells don’t have extremely variable antigen-specific receptors like other lymphoid lineage cells  Killer activation receptors (KARs)- recognize presence of stress-related molecules (called MICA & MICB molecules in humans) expressed by host cells that are unhealthy or infected  Binding of MICA or MICB molecules by NK cell’s KARs induces NK cell to attach & destroy the targeted (e.g., infected) host cell  Killer inhibition receptors (KIRs)- monitor major histocompatibility complex (MHC) class I molecules normally displayed on cell surfaces of all nucleated cells in the body  Determine normality of host cells; cancer & viruses decrease MHC class I  Once bound to a target cell via its KARs, KIRs assess expression of MHC class I molecules on that cell  If subnormal MHC I= target cell killed  If normal MHC I= target cell is released  Inflammation, innate immunity, and lymphoid cells 3-23 NK cells and macrophages activate each other at sites of infection Interaction between an NK cell & macrophage induces NK-cell proliferation & differentiation  INTERACTIONS BETWEEN DENDRITIC CELLS & NK CELLS INFLUENCE THE IMMUNE RESPONSE  Left- In virus-infected tissue, an immature dendritic cell expressing viral antigens can activate NK cells & drive their differentiation into effector cells (kill!)  Center- When activated cytotoxic NK cells are abundant & innate immunity is overcoming infection, NK cells kill dendritic cells & prevent their activation of adaptive immunity  Right- When NK cells are scarce & innate immunity cannot control infection, NK cells induce dendritic cells to differentiate into a form that migrates to secondary lymphoid tissue & initiates the adaptive immune response  Inflammation, innate immunity, and lymphoid cells 3-25 The NK-cell population retains a memory of its encounters with pathogens For example: Time course of the NK-cell response to human cytomegalovirus (CMV)  WHY SHOULD YOU CARE?  The immune system must be able to distinguish its own molecules, cells, & organs (self) from those of foreign origin (nonself)  Innate immune system does this by expressing germline-encoded pattern recognition receptors (PRRs) on the surface of its cells that recognize structures on potentially invasive organisms  Adaptive immune system uses somatically generated epitope-specific T-cell and B-cell receptors (TCRs & BCRs) TWO BRANCHES OF THE IMMUNE SYSTEM INNATE VS. ADAPTIVE IMMUNITY   Primary lymphoid organs- where immune cells develop  Bone Marrow THE  Thymus LYMPHATIC  Secondary lymphoid organs- where immune response is initiated SYSTEM  Lymph Nodes  Spleen  Barrier tissues  Tertiary lymphoid organs- also organize & maintain an immune response Figure 1.21 Location of lymphoid tissues in the human body Please review DITKI lymph node, spleen, and bone marrow- you could see questions related to this on Exam 2 Figure 1.22 Lymphocyte recirculation 1.Circulating lymphocytes leave in efferent lymph 2.Return to blood in left subclavian vein 3.Enter lymph node through walls of fine capillaries in secondary lymphoid organs Figure 1.23 Recirculating lymphocytes meet lymph-borne pathogens in draining lymph nodes Lymphocytes activated by specific antigen stay in LN to divide & differentiate into effector cells With B cells, this is how we get germinal centers Lymphocytes not activated by specific antigen leave LN in efferent lymph & are carried by lymphatics to thoracic duct & into the blood Elements of the Immune System and Their Roles in Defense 1-12 Adaptive immunity is initiated in secondary lymphoid tissues Figure 1.24 Architecture of the lymph node, the site where blood-borne lymphocytes respond to lymph-borne pathogens  SECONDARY LYMPHOID TISSUE- LYMPH NODES  Lymph nodes are responsible for filtering & processing antigens present in lymphatic fluid as it travels from Afferent to Efferent vessels  Activation into effector cells takes place in follicles of secondary lymphoid organs  T lymphocytes  CD4+ helper T cells assist in B-cell activation  CD8+ cytotoxic T cells that attack & destroy virally infected cells  B lymphocytes further mature in germinal centers  Antigen affinity is increased  Class switching can take place  Both B & T lymphocytes will develop into long lived memory cells in these areas Figure 1.25 Activation of adaptive immunity in a draining lymph node 1. Pathogens & antigens (& dendritic cells carrying pathogens & antigens) arrive at a lymph node in afferent lymph draining the infected tissue 2. Pathogens & debris are removed by macrophages 3. Dendritic cells become residents & move to T-cell areas, where they encounter small lymphocytes that have entered LN from blood (green) 4. Dendritic cells orchestrate division & differentiation of small pathogen-specific lymphocytes into effector cells (blue)  Some helper & cytotoxic T cells leave in efferent lymph & travel to infected tissue  Other helper T cells stay in LN to stimulate division of pathogen-specific B cells & their differentiation into plasma cells (yellow) (B cell follicles → germinal centers) 5. Plasma cells move into medulla of lymph node, where they secrete pathogen-specific antibodies  Other plasma cells leave LN & travel to bone marrow, where they secrete pathogen-specific antibody in quantity 6. Antibodies travel to infected tissue by efferent lymph & blood  SECONDARY LYMPHOID TISSUE-SPLEEN  Spleen is first line of defense against blood-borne pathogens  Consists of two different tissues:  Red pulp- where old and damaged red blood cells are removed from circulation  Most of spleen is red pulp  White Pulp- where white blood cells reside  A specialized region of macrophages & B cells known as the marginal zone borders white pulp & separates it from red pulp Figure 1.26 The spleen has organized aggregations of lymphocytes like those present in lymph nodes  Situated in upper left part of the abdomen, the spleen weighs ~150 g & is larger than any lymph node  Upper diagram depicts a section of spleen in which nodules of white pulp are scattered within the more extensive red pulp.  Lower diagram shows a nodule of white pulp in transverse section  Comprises a sheath of lymphocytes surrounding a central arteriole  In the periarteriolar lymphoid sheath (PALS), the lymphocytes near the arteriole are mostly T cells (blue region), whereas B cells (yellow regions) are situated peripherally  Lymphoid follicles comprise a germinal center, a B-cell corona, and a marginal zone containing macrophages & differentiating B cells  Perifollicular zone- contains erythrocytes, macrophages, T cells, & B cells  ALSO A SCIENTIST  Viki Male, PhD  “Quite recently, it turned out that there is a special kind of NK cell that is only found in the liver, and my group showed that these special NK cells can’t ever leave the liver – they are liver-resident. The thing is, we still don’t know what they do. There is some evidence that they could act as an early warning system for certain viruses that particularly infect the liver, but I think they might also do something important in the healthy liver.”  https://thefemalescientist.com/portrait/viki- male/1670/meet-viki-male-an-immunologist- working-out-what-nk-cells-do-in-the-liver/  ALSO A SCIENTIST  Amintinder “Miti” Kaur, MD  Professor of Microbiology and Immunology  Chair, Division of Immunology, Tulane National Primate Research Center  Immunomodulatory role of Natural Killer T cells  First characterization of natural killer T (NKT) cells in sooty mangabeys and the novel finding that mangabeys differ from other species including mice, humans and macaques, in lacking CD4+ NKT cells. As a result, SIV-infected mangabeys are protected from NKT cell depletion and dysfunction.  We are currently investigating the immunoregulatory functions of NKT cells in modulating the immunogenicity and efficacy of candidate AIDS vaccines and affecting the outcome of SIV infection