IMMU2011 - Weeks 6-7

Why does the body need killer lymphocytes?

to eliminate cells infected with intracellular microbes or transformed into tumour cells, particularly when microbes evade phagocytic killing by living in the cytosol or non-phagocytic cells

What are the two types of killer lymphocytes?

Natural Killer (NK) cells (innate immunity) and CD8+ cytotoxic T lymphocytes (CTLs) (adaptive immunity)

What is the primary effector function of CD8+ T cells?

to directly kill infected or tumour cells and produce cytokines like IFN-γ that activate other immune cells.

How are CD8+ T cells activated?

they are activated by recognising antigen presented on MHC class I molecules by dendritic cells in lymphoid organs, receiving co-stimulation, and differentiating into effector CTLs and memory cells

What happens during the effector phase of CD8+ T cell responses?

CTLs migrate to infection or tumor sites, recognize infected cells, and kill them via granule release or death receptor pathways

What are the main cytotoxic proteins in CTLs and NK cells?

perforin (forms pores in the target cell membrane) and granzymes (serine proteases that trigger apoptosis)

How does perforin aid in target cell killing?

perforin forms pores in the target cell membrane to allow granzymes entry into the cytosol

What does granzyme B do in target cells?

it activates caspases and initiates apoptosis

What is the FAS-FASL pathway?

a granule-independent killing mechanism where FasL on killer cells binds to Fas on target cells, triggering apoptosis via caspases

Why are CTLs not damaged during target cell killing?

they direct granules specifically into target cells and express cathepsin B, which degrades any perforin that might affect the CTL

What cytokine do CD8+ T cells produce and what is its function?

IFN-γ, which activates macrophages and contributes to clearing phagocytosed microbes

What are NK cells and what is their origin?

innate cytotoxic lymphocytes derived from the bone marrow that do not require prior sensitisation to kill

How do NK cells recognize their targets?

via a balance of activating and inhibitory signals, including detection of missing or altered MHC class I and stress-induced ligands

What is 'missing-self' recognition?

a mechanism by which NK cells recognize and kill cells lacking MHC class I molecules

What is 'stress-induced self'?

a mechanism where NK cells are activated by ligands upregulated on stressed or damaged cells

What are two main functions of NK cells?

killing infected or tumor cells and producing IFN-γ

What is Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)?

a process where NK cells recognize antibody-coated cells via FcγRIII (CD16) and kill them

Why is immunological memory important?

it forms the basis of vaccination and provides faster, more robust responses upon re-exposure to antigens

What are key features of memory cells?

stemness (ability to differentiate), longevity, and robustness in response

How are memory B cells generated?

primarily in germinal centers after T cell-dependent activation, involving class switching and affinity maturation

What is the difference between T-dependent and T-independent B cell responses?

T-independent responses generate short-lived IgM without memory; T-dependent responses produce class-switched, high-affinity memory B cells

What do memory B cells do upon re-exposure to antigen?

rapidly produce large amounts of high-affinity, isotype-switched antibodies

What are the stages of humoral immunity?

Extrafollicular Response - rapid IgM secretion, no memory. Germinal Centre Response - class switching, affinity maturation, memory and long-lived plasma cell formation. Memory Phase - rapid secondary response without antigen. Plasma Cell Phase - long-lived antibody secretion from bone marrow.

What is the role of follicular dendritic cells (FDCs)?

they present antigen-antibody complexes to B cells in germinal centers, promoting selection of high-affinity B cells

What is affinity maturation?

a process where B cells undergo somatic hypermutation to increase antibody affinity for antigen

What drives class switching in B cells?

signals from T cells via CD40L and cytokines

Why is class switching important?

it enables antibodies to perform diverse functions depending on the isotype (e.g., IgG, IgA, IgE)

What are memory T cells and how are they formed?

long-lived T cells formed after antigen encounter; some effector cells transition into memory precursors

What are the three subsets of memory T cells?

1. Central Memory (TCM): circulate in lymphoid tissues, express CCR7/CD62L, highly proliferative. 2. Effector Memory (TEM): circulate in peripheral tissues, rapid response, lack CCR7/CD62L. 3. Resident Memory (TRM): remain in tissues like skin/mucosa, provide localised protection, express CD69/CD103.

What cytokines maintain memory T cells?

IL-7 and IL-15, which support survival and homeostatic proliferation

What are cytokines?

low-molecular-weight proteins produced by cells that act on themselves or other cells by binding to surface receptors, regulating immune responses

What do cytokines do?

they mediate and regulate innate and adaptive immunity and stimulate hematopoiesis

How are cytokines produced?

they are not stored but synthesised rapidly upon stimulation; their gene expression is transient, and mRNA is unstable to limit their activity

How do cytokines exert their effects?

by binding to specific membrane-bound receptors composed of transmembrane proteins with extracellular cytokine-binding domains and intracellular signalling domains

What are the major types of cytokines?

interleukins (IL), Interferons (IFN), Tumor Necrosis Factors (TNF), and growth factors like GM-CSF

What are the three major functions of cytokines?

regulation of innate immunity, regulation of adaptive immunity, and stimulation of hematopoiesis

What is pleiotropy in cytokines?

one cytokine can act on multiple different target cell types

What is redundancy in cytokines?

multiple cytokines can produce the same effect

What is synergy in cytokines?

the combined effect of two or more cytokines is greater than the sum of their individual effects

What is antagonism in cytokines?

one cytokine inhibits the effect of another

What regulates cytokine activity?

short half-life, regulated receptor expression, and proximity between producing and responding cells

What are interferons (IFNs)?

pleiotropic cytokines critical in antiviral and intracellular pathogen defense, classified into type I (α, β), type II (γ), and type III (λ)

What is the main action of type I interferons?

produced by tissue and innate immune cells; act in a paracrine manner to protect neighboring uninfected cells from viral infection

What is the function of type II interferon (IFN-γ)?

produced by activated lymphocytes; activates phagocytes, enhances MHC expression, and promotes microbial killing

What is TNF (Tumor Necrosis Factor)?

a key mediator of acute inflammation, primarily produced in response to bacterial infection; induces fever, chemokine production, and endothelial activation

What are the local effects of TNF?

stimulates recruitment and activation of neutrophils and monocytes, upregulates endothelial adhesion molecules, and promotes DC migration to lymph nodes

What are the systemic effects of TNF?

induces fever (via hypothalamus), acute-phase proteins (via liver), and muscle/fat catabolism (cachexia)

What are the pathogenic effects of TNF?

in high concentrations, TNF causes septic shock symptoms: hypotension, metabolic disturbances, and disseminated intravascular coagulation

What are chemokines?

chemoattractant cytokines that direct leukocyte movement and tissue positioning, classified into CC, CXC, C, and CX3C families

What do chemokine receptors do?

expressed on leukocytes; recognize chemokine gradients and direct cell migration by increasing integrin affinity and cytoskeletal changes

What roles do chemokines play in immune responses?

direct leukocyte trafficking, support lymphoid tissue development, and assist DC migration to lymph nodes

What are CCR5 and CXCR4?

chemokine receptors that also serve as HIV co-receptors

How do immune cells communicate?

via direct cell contact (e.g., receptor-ligand binding) and indirectly via soluble signals like cytokines and chemokines

What is the difference between lymphoid and non-lymphoid tissues?

lymphoid tissues support immune cell activation and include primary (e.g., bone marrow, thymus) and secondary (e.g., lymph nodes, spleen) organs, whereas non-lymphoid tissues are typically peripheral tissues like skin and mucosa

What is cell-contact dependent communication?

occurs through direct receptor-ligand interactions between immune cells

What is cell-contact independent communication?

occurs through soluble factors such as cytokines and chemokines

Why do leukocytes need to migrate?

to reach tissues where infection is present and to allow immune surveillance through circulation between lymphoid tissues and the blood

What are adhesion molecules?

cell surface proteins that mediate leukocyte binding to endothelium, facilitating their exit from blood vessels

What are the two main classes of adhesion molecules?

selectins (mediate rolling) and integrins (mediate firm adhesion)

What are selectins?

carbohydrate-binding proteins (e.g., E-, P-, L-selectin) on endothelial and immune cells that mediate initial weak interactions

What are integrins?

heterodimeric proteins that increase affinity in response to chemokines and allow firm adhesion of leukocytes to endothelium

What triggers integrin activation?

chemokine binding to leukocyte receptors causes cytoskeletal rearrangement and increases integrin affinity

What is leukocyte rolling?

initial weak adhesion to endothelial cells via selectins that slows the leukocyte

What is leukocyte arrest?

firm integrin-mediated binding to endothelium that halts leukocyte movement before transmigration

What is extravasation?

leukocyte migration across the endothelium into tissue

How do leukocytes know where to go?

chemokine gradients and expression of adhesion molecules guide them to sites of infection or lymphoid organs

What are High Endothelial Venules (HEVs)?

specialised postcapillary venules in secondary lymphoid tissues that allow lymphocyte entry; express addressins like PNAd

How do naive T cells enter lymph nodes?

via HEVs, using L-selectin (binds PNAd), CCR7 (binds CCL19/21), and LFA-1 (binds ICAM-1) to home and adhere

What is lymphocyte recirculation?

the continuous movement of lymphocytes between blood and lymphoid tissues to maximize antigen encounter opportunities

How do naive T cells return to the blood?

via efferent lymphatics to the thoracic duct or right lymphatic duct, then into the bloodstream

What is S1PR1 and how does it regulate lymphocyte egress?

a receptor that senses sphingosine-1-phosphate (S1P) gradients; re-expressed on naive T cells after failing to find antigen, allowing them to exit lymph nodes

What maintains the S1P gradient?

S1P lyase degrades S1P in tissues, keeping levels low in lymph nodes and high in lymph/blood

What are the markers of naive T cells that help in lymph node entry?

CD4/CD8, TCR, CCR7, L-selectin, and LFA-1