Integrated Dynamics of Innate and Adaptive Immunity PDF

Integrated Dynamics of Innate and Adaptive Immunity Literature: Chapter 11, Janeway’s Immunobiology ETH Zurich Lecture on “Pharmaceutical Immunology I” Prof. Dr. Cornelia Halin Winter 535-0830-00L HS 2024 Content 1. Integration of innate and adaptive immunity in...

Integrated Dynamics of Innate and Adaptive Immunity Literature: Chapter 11, Janeway’s Immunobiology ETH Zurich Lecture on “Pharmaceutical Immunology I” Prof. Dr. Cornelia Halin Winter 535-0830-00L HS 2024 Content 1. Integration of innate and adaptive immunity in response to specific types of pathogens 2. Effector T cells augment the effector functions of innate immune cells 3. Immunological memory 1  Revision form Chapter 1 Course of a typical infection that is cleared by innate and adaptive immunity min - days days days - weeks potentially at least life-long 5-7 days Þ In this Chapter we will focus on how the innate and adaptive immune system establish specific, effective and long-lasting responses towards different types of pathogens 2  1. Immune Integration Infections and the response to them can be divided into a series of stages 3  1. Immune Integration Both innate and adaptive immunity is needed to overcome an infection SCID: severe combined immunodeficiency (e.g. lacking the common gamma chain (CD132), which forms part of many cytokine receptors (e.g. receptors of IL-2, IL-7, IL-15, IL-21) RAG: recombination activating gene 1 or 2 (important for rearrangement of B cell and T cell receptor gene segments) What do the green and red curves tell you? How can one explain this? What would be the consequences for humans lacking any of these cell types? 4 PMN: polymorph nuclear cells; MAC: macrophages  1. Immune Integration Different type of infections require different type of T helper cells => But how does the immune system “know” which type 5 of response needs to be induced?  1. Immune Integration Remember: Correct differentiation of T cells into effector cells requires the presence of three (3) signals => The cytokines of signal 3 vary, depending on the type of challenge / stimulus (e.g. type of infection) Innate cy s lymphoid tok kine cells ine o cyt s DCs, macrophages, Sensor epithelial cells, T cell differentiation 6 fibroblasts cells cytokines  Role of innate lymphoid cells (ILCs) in adaptive immunity arise from the lymphoid lineage (common lymphoid precursors) but lack specific antigen recognition receptors subgroup defined on the basis of their cytokine production Natural Killer (NK) cells are the best-described ILC subset (=> Chapter 3) most ILC1-3 live in (barrier) tissues, where they contribute to innate host defense by cytokine production. They also have an important role in steering the developing adaptive T cell response (=> determine T helper cell differentiation) TH1 TH2 TH17 7  1. Immune Integration Innate lymphoid cells (ILCs) are activated by cytokines produced by innate sensor cells 1) Amplify and coordinate the local innate response (e.g. leukocyte recruitment): allow to clear many infections by solely non-adaptive mechanisms “buy time” for the induction of adaptive immunity 2) Influence development of a distinct type of T helper cells (TH1, TH2, TH17) TH1 TH2 TH17 => ILCs produce the same cytokines as the corresponding TH subtype – but they produce them earlier during the immune response! 8  2. Effector cell function 2. Functions of different effector cell types TH1 cells: Fight intracellular bacteria / protozoa TH2 cells: Fight parasites, e.g. intestinal helminths (& cause allergic disease) TH17 cells: Fight extracellular bacteria and fungi TFH cells: Support B cell activation/differentiation Treg cells: Suppress overshooting / autoimmune responses Cytotoxic CD8+ T cells (CTLs): Kill virally infected cells and tumor cells 9  2. Effector cell function TH1 cells coordinate and amplify the host response to intracellular pathogens through classical activation of macrophages Many intracellular pathogens (e.g. mycobacteria tuberculosis, salmonella, protozoa like leishmania) survive in macrophages by preventing the fusion of the phagosome and the lysosome When a pathogen-specific TH1 cell recognizes its peptide on MHCII of an infected macrophage, it is induced to secrete IFNg and to express CD40L. Both signals, i.e. secreted IFNg and CD40/CD40L interaction, are required for full-fledged macrophage activation, resulting in phagosome / lysosome fusion and pathogen destruction. 10  2. Effector cell function TH1-activated macrophages: Enhanced antimicrobial effectiveness of macrophages and further amplification of the immune response In addition to inducing fusion of the phagosome and the lysosome, TH1-activation of macrophages leads to: production of reactive oxygen species (ROS) Secretion of TNFa and IL-12 upregulation of MHC and costimulatory molecules 11 Chronic TH1-activation of macrophages: Formation of granulomas to contain intracellular pathogens that cannot be cleared some intracellular bacteria, e.g. mycobacterium tuberculosis, and protozoa (e.g. leishmania) are highly resistant to microbicidal effects of activated macrophages results in chronic low-level infection that requires constant TH1 support if TH1 response is defective; systemic spread of the disease (fatal) Granuloma tissue comprises: comprises a core of infected macrophages (fused “giant cells”) and a rim of T cells serves to “wall-off” the pathogens that resist destruction typical feature of tuberculosis 12  2. Effector cell function TH2 cells coordinate type 2 responses to expel intestinal helminths and repair tissue injury Helminths: range from 1mm – 1m too big to be killed or engulfed by a single leukocyte Major focus of anti-helminth TH2 response: Expel the worm (causing diarrhea, vomiting, increased intestinal peristalsis) Limit the tissue damage the helminths cause when invading the host Th2 responses lead to: Production of high IgE levels by B cells: Induce mast cell degranulation Induce release of cytotoxic granules by eosinophils Recruitment of type 2 cells: eosinophils, mast cells, M2 macrophages, TH2 cells Epithelial repair and mucus production (IL13) 13 TH2 responses in allergic disease Allergy: Adaptive immune response against an innocuous foreign substance (e.g. tree pollen) Involves activation of TH2 cells and production of IgE antibodies IgE-crosslinking on mast cells leads to a rapid release of granules containing histamine and other inflammatory mediators and secretion of lipid mediators Common anti-allergic drugs: Anti-histamins: block histamin receptors Mast cell stabilizers block degranulation (e.g. cromoglicic acid) 14  2. Effector cell function TH17 cells enhance the clearance of extracellular bacteria and fungi Example: infections with Staph. aureus Activated TH17 cells: secrete IL-17 => via action of downstream mediators, IL-17 enhances production of neutrophils in the bone marrow and recruitment to site of infection secrete IL-22 => acts on epithelial cells to produce antimicrobial peptides induce production of pathogen-specific antibodies; opsonization of bacteria/fungi and destruction by neutrophils or https://www.verywellhealth.com /staph-skin-infections-and- macrophages: mrsa-2633409 clearance of pyogenic (puss-forming) bacteria like Staphylococcus aureus and https://www.dermatolo Streptococcus pneumoniae requires gytimes.com/view/imm antibodies, macrophages and neutrophils unotherapies- staphylococcus- aureus 15  3. Immunologic memory 3. Immunologic Memory Remember: After an infection has been cleared, most effector T cells undergo cell death B cells: some plasma cells can remain and Memory B cells are long produce antibodies for many years lived, hardly divide and express some surface anti- Small populations of specialized memory T & bodies. They are rapidly activated during antigen re- B cells, that were formed during the adaptive challenge (secondary immune response remain exposure) Memory cells can persist in the absence of the antigen that originally induced them Proof of concept: Smallpox vaccination Smallpox were eradicated in 1978 => Can assume that this is a true memory response (out-rule reinfection) 16 How can one detect antigen-specific T cells? Tetramer technology: - Tetramers are composed of biotinylated peptide-MHC molecules - Peptide-MHC is bound via biotin to strepatividin => tetravalent => higher binding affinity for T cell receptor - Fluorescently labelled (example: PE) => can be used like an antibody in flow cytometry https://www.mblbio.com/bio/g/support/faq_MHC_General.html  3. Immunologic Memory Kinetics of T cell expansion/contraction after infection Experiment: mice were infected with Listeria monocytogenes and the number of listeriolysin (LLO) toxin-specific CD4+ T cells was monitored in blood over time using MHC Tetramer Technology Day 0: 100 cells 1000 x Day 7: 100’000 effector cells Day 25: 7’000 memory cells Day 450: 500 memory cells 18  3. Immunologic Memory Memory B cell responses are more rapid and have higher affinity for antigen compared with responses of naïve B cells 19  3. Immunologic Memory Both the affinity and the amount of antibody increases after repeated immunization The increase in affinity is explained by the fact that memory B cells can re-enter germinal centers and undergo additional somatic hypermutation and affinity maturation during secondary immune responses. 20  Exercise on tetanus vaccination Vaccines are available that can help prevent tetanus, an infection caused by Clostridium tetani bacteria. The vaccine contains the inactivated tetanus toxoid (see Chapter 10, p.29), together with an adjuvants (see Chapter 3, p. 25). https://www.cdc.gov/vaccines/vpd/tetanus/index.html 1) Imagine you are injected with a tetanus vaccine into your upper forearm: What are the immunologic processes that take place subsequently? 2) Why does this vaccine need an adjuvants (typically alum)? 3) Why does tetanus vaccination need to be repeated every 10 years? – Which type of recall-responses are induced upon repeated immunization?  Take-home message The innate immune system serves to provide immediate response to pathogen and – if needed - to keep infections low until adaptive immunity has been initiated Innate lymphoid cells (ILCs) bridge between the innate and adaptive immune system and skew the adaptive T cell response towards the type needed. Adaptive immunity is induced in lymphoid tissues in contact with the site of infection and involves massive expansion of antigen-specific lymphocytes The differentiated effector T cells are equipped with effector functions and the trafficking molecules needed to reach the sites of infection Once the infection has been cleared, most effector cells dye, but a small population of memory cells and elevated antibody titers remain to guarantee rapid recall responses in case of reinfection. 22