Untitled

• The lecture discusses the integrated dynamics of innate and adaptive immunity.
• Chapter 11 of Janeway's Immunobiology serves as literature.
• The lecture addresses the integration of innate and adaptive immunity in response to specific pathogens.
• The lecture addresses how effector T cells augment the functions of innate immune cells and immunological memory.

Course of a Typical Infection

• A typical infection cleared by innate and adaptive immunity occurs in phases
• Establishment of infection is the first phase
• Inductive phase is second
• Effector phase is third
• Memory phase is fourth
• The innate immune response handles the initial infection
• Adaptive immune response comes later
• The focus is placed on how the innate and adaptive immune systems establish specific, effective, and long-lasting responses to pathogens.

Stages of Infection Response

• Infections and responses are divided into stages: local infection with epithelial penetration, local tissue infection, lymphatic spread, and adaptive immunity.
• In local infection, wound healing occurs, antimicrobial proteins/peptides, phagocytes, and complement destroy invading microorganisms.
• During local infection of tissues, complement is activated, dendritic cells migrate to lymph nodes, phagocytes function, NK cells activate, and cytokines/chemokines are produced.
• Lymphatic spread pathogens are trapped, phagocytosed in lymphoid tissue, and adaptive immunity is initiated by migrating dendritic cells.
• For adaptive immunity, infection is cleared by specific antibodies, T-cell-dependent macrophage activation, and cytotoxic T cells.

Innate and Adaptive Immunity

• Both innate and adaptive immunity are necessary to overcome infection.
• SCID is severe combined immunodeficiency, like lacking the common gamma chain (CD132).
• CD132 forms part of many cytokine receptors (receptors of IL-2, IL-7, IL-15, IL-21).
• RAG is recombination activating gene 1 or 2, important for B cell and T cell receptor gene segment rearrangement.

T Helper Cells

• Different infections require different T helper cells.
• T helper (TH) cells consist of TH1, TH2, TH17, TFH, and Treg cells.
• TH1 cells act on macrophages, targeting intracellular bacteria, with IFN-γ as the major cytokine.
• TH2 cells target bone marrow and goblet cells, targeting helminth parasites, with IL-4, IL-5, and IL-13 cytokines.
• TH17 cells target stromal and epithelial cells, targeting extracellular bacteria, with cytokines like IL-17 and IL-22.
• TFH cells act on B cells and encourage isotype switching and affinity maturation.
• Treg cells act on dendritic cells, suppressing T-cell activation.

T Cell Differentiation

• Proper T-cell differentiation into effector cells needs three signals.
• Signal 3 cytokines vary depending on the challenge.

Innate Lymphoid Cells (ILCs)

• Innate Lymphoid Cells (ILCs) come from lymphoid lineage (common lymphoid precursors) but lack antigen recognition receptors.
• ILC subgroups are defined by cytokine production.
• Natural Killer (NK) cells are the best-described ILC subset.
• Most ILCs live in tissues, contributing to host defense through cytokine production and steering adaptive T cell response.
• ILCs also amplify/coordinate the local innate response.
• They help clear infections by non-adaptive mechanisms and "buy time" for adaptive immunity.
• ILCs influence developing distinct T helper cell types (TH1, TH2, TH17).
• ILCs produce the same cytokines as the matching TH subtype earlier during immune response.
• NK cells induce immunity against viruses and intracellular pathogens.
• ILC1 cells defends against viruses and intracellular pathogens.
• ILC2 causes expulsion of extracellular parasites.
• ILC3 and LTi cells induce immunity to extracellular bacteria and fungi.
• ILCs are activated by cytokines made by innate sensor cells.

Effector Cell Function

• TH1 cells fight intracellular bacteria/protozoa.
• TH2 cells fight parasites like intestinal helminths and cause allergic disease.
• TH17 cells fight extracellular bacteria/fungi.
• TFH cells support B cell activation/differentiation.
• Treg cells suppress overshooting/autoimmune responses.
• Cytotoxic CD8+ T cells (CTLs) kill virally infected/tumor cells.

Macrophages

• TH1 cells coordinate and amplify host response to intracellular pathogens via classical macrophage activation.
• Many intracellular pathogens survive in macrophages by preventing phagosome/lysosome fusion.
• Pathogen-specific TH1 cells secrete IFNy, express CD40L, and recognize peptides on MHCII of infected macrophages.
• Both signals, i.e. secreted IFNy and CD40/CD40L interaction, are needed for full macrophage activation, leading to phagosome/lysosome fusion releasing destruction of pathogens.
• TH1-activated macrophages enhance antimicrobial activity and the immune response.
• TH1-activation of macrophages leads to ROS production.
• TH1-activation of macrophages leads to TNFα and IL-12 secretion.
• TH1-activation of macrophages leads to MHC and costimulatory molecule upregulation.

Granulomas

• Chronic TH1-activation of macrophages leads to granuloma formation to contain intracellular pathogens that can't be cleared.
• Some intracellular bacteria (e.g. M. tuberculosis) and protozoa (e.g. leishmania) resist microbicidal effects of activated macrophages.
• Chronic low-level infections are a result and require constant TH1 support.
• Defective TH1 response can cause systemic spread and disease.
• Granuloma tissue includes a core of infected macrophages and a T cell rim, walling off the pathogen and is a feature of tuberculosis.

Helminths

• TH2 cells coordinate type 2 responses to remove intestinal helminths and repair tissue injury.
• Helminths range from 1mm-1m and are too large to be killed/engulfed by leukocytes.
• The major focus of anti-helminth TH2 response expels the worm by causing diarrhea, vomiting, and increased intestinal peristalsis.
• The major focus of anti-helminth TH2 response limits tissue damage caused by helminths.
• Th2 responses lead to high IgE levels made by B cells and induces mast cell degranulation.
• Th2 induces release of cytotoxic granules by eosinophils, and recruits Type 2 cells.
• Th2 controls Epithelial repair and mucus production (IL13)

Allergy

• TH2 responses include adaptive immune response against an innocuous foreign substance such as tree pollen.
• TH2 responses include cells and production of IgE antibodies are activated during the response.
• IgE-crosslinking on mast cells causes the quick release of granules with histamine, inflammatory mediators, and lipid secretion.
• Common anti-allergic drugs antihistamines which block histamin receptors.
• Common anti-allergic drugs mast cell stabilizers block degranulation.

Extracellular TH17 Cell Function

• Activated TH17 enhances the clearance of extracellular bacteria and fungi .
• Activated TH17 cells secrete IL-17.
• IL-17 enhances production of neutrophils in bone marrow and their recruitment to infection sites.
• Activated TH17 cells secrete IL-22: acts on epithelial cells to produce antimicrobial peptides.
• Activated TH17 cells induce production of pathogen-specific antibodies, opsonization of bacteria/fungi leading to destruction by neutrophils/macrophages.
• TH17 clears pyogenic (puss-forming) bacteria such as Staphylococcus aureus and Streptococcus pneumoniae, requiring antibodies, macrophages, and neutrophils.

Immunologic Memory

• After an infection is cleared, most effector T cells undergo cell death.
• After an infection is cleared, some B cells/plasma cells remain, producing antibodies for years.
• After an infection is cleared, small populations of specialized memory T/B cells stay.
• Memory cells persist even without the antigen that originally induced them.
• Smallpox eradication in 1978 provides proof through smallpox vaccination.
• The true memory response is assuming an out-rule reinfection.
• Memory B cells are long-lived, divide little, express some surface antibodies, and activate rapidly during secondary antigen re-exposure.

Tetramer Technology

• Tetramer technology is a way to detect antigen-specific T cells.
• Tetramers are biotinylated peptide-MHC molecules.
• Peptide-MHC binds via biotin to streptavidin, creating a tetravalent structure with higher binding affinity for the T cell receptor.
• Tetramers are fluorescently labeled and can be used like an antibody in flow cytometry.

T Cell Expansion and Contraction

• In mice infected with Listeria monocytogenes, listeriolysin (LLO) toxin-specific CD4+ T cells are monitored, revealing an T cell expansion and contraction after infection.
• Day 0 there are 100 cells
• Day 7 there are 100'000 effector cells
• Day 25 there are 7'000 memory cells
• Day 450 there are 500 memory cells

Memory B Cells

• Memory B cell responses are faster and have a higher affinity for antigens than naive B cells.
• Memory B cells have a 1:10² - 1:10³ frequency of antigen-specific B cells compared to unimmunized B cells.
• Memory B cells produce IgG and IgA isotype antibodies compared to unimmunized B cells.
• Memory B cells have high affinity compared to unimmunized B cells.
• Memory B cells are likely to have somatic hypermutation compared to unimmunized B cells.
• Both the affinity and amount of antibody is boosted after repeat immunization.

B Cells

• The boosted affinity comes from memory B cells re-entering germinal centers, leading to extra somatic hypermutation and affinity maturation during secondary immune responses.

Immunization

• Vaccines, containing inactivated tetanus toxoid, help prevent tetanus (caused by Clostridium tetani).
• Adjuvants are needed in vaccines.
• Tetanus vaccination needs to be repeated because repeated immunization causes certain recall-responses.

Take Home Message

• The innate immune system responses immediately and keeps infections low until the adaptive system initiates.
• Innate lymphoid connects to and affects between the innate and adaptive immune systems.
• Adaptive immunity happens in lymphoid tissues near the infection site, creating a large expansion of antigen-specific lymphocytes.
• Differentiated effector T cells are armed with molecules needed to get to the infection locations.
• Once clear, most effector cells dye, but a few memory cells and higher antibody levels are left to protect for the future from reinfection.