Core Concepts in Immunology

Abstract

The immune system is constantly engaged in maintaining homeostasis while poised to respond to signs of damage or danger. Immunological homeostasis is disturbed by tissue damage and growth abnormalities as well as by infection. Throughout the body, epithelial cells and immune-surveillant cells are equipped with specific receptors to detect these signs and respond with a complex, interacting set of defense mechanisms. Highly conserved primordial “identify and destroy” strategies characterize innate immunity, while more sophisticated detection and targeted killing processes, that display exquisite specificity, multiple layers of regulation, and memory, characterize adaptive immunity. In this chapter, the fundamental concepts of innate and adaptive immunity and their interaction are briefly reviewed. Further details on individual topics can be obtained in the reviews cited.

Appendices

Appendix 2.1: Relevant Cluster of Differentiation (CD) Antigens

CD1	MHC class I-like lipid-presenting molecule expressed by APCs and other cells
CD2	Adhesion/costimulatory molecule expressed by T cells and NK cells
CD3	TCR-associated molecular complex necessary for TCR-mediated signal transduction
CD4	Co-receptor for MHC class II molecules found on T cells, monocytes, and macrophages
CD8	Co-receptor for MHC class I molecules found on T cells and some NK cells
CD11	Family of adhesion molecules found on lymphocytes, granulocytes, monocytes, and macrophages
CD14	Receptor for lipopolysaccharide and other molecules found on DC and macrophages
CD16	Immunoglobulin Fc receptor found on neutrophils, macrophages, and NK cells
CD18	Adhesion molecule found on leukocytes that associates with CD11
CD19	Costimulatory receptor found on B cells
CD20	Costimulatory receptor found on B cells
CD25	High-affinity IL-2 receptor (α-chain) found on activated T cells, B cells, and monocytes
CD28	Naïve T-cell receptor for costimulatory molecules CD80 and CD86
CD34	Adhesion molecule found on hematopoietic precursors
CD35	Complement receptor found on most leukocytes
CD40	B-cell receptor for costimulatory molecule CD154
CD44	Leukocyte adhesion molecule
CD45	Signaling molecule that augments signals through T-cell and B-cell antigen receptors
CD49	Family of adhesion molecules found on leukocytes
CD50	Family of adhesion molecules found on leukocytes
CD54	Family of adhesion molecules found on hematopoietic cells
CD56	Adhesion molecule found on NK cells
CD58	Adhesion molecules found on hematopoietic cells CD64 immunoglobulin Fc receptor found on monocytes and macrophages
CD69	Lectin of unknown function found on activated T cells, B cells, NK cells, and macrophages
CD74	MHC class II chaperone molecule found in APCs
CD79	B-cell antigen receptor-associated molecular complex required for Ig-mediated signal transduction
CD80	Costimulatory molecule found on APCs
CD81	B-cell co-receptor
CD86	Costimulatory molecule found on APCs
CD94	Stimulatory/inhibitory receptor for HLA-E found on NK cells and some T cells
CD95	Apoptosis-inducing molecule found on a wide variety of cells (Fas)
CD102	Adhesion molecule found on resting lymphocytes, monocytes, and endothelial cells
CD106	Adhesion molecule found on endothelial cells
CD116	Receptor for granulocyte–macrophage colony-stimulating factor found on myeloid cells
CD117	Stem cell factor receptor found on hematopoietic cell precursors
CD119	IFN-γ receptor found on macrophages, monocytes, and B cells
CD120	TNF-α and -β receptor found on many cell types
CD121	IL-1 receptor found on T cells, B cells, macrophages, and monocytes
CD122	IL-2 receptor β-chain found on NK cells and some T cells and B cells
CD124	IL-4 receptor found on mature T cells and B cells
CD125	IL-5 receptor found on eosinophils, basophils, and activated B cells
CD132	Common γ-chain receptor for IL-2, IL-4, IL-7, IL-9, and IL-15; CD134 costimulatory molecule found on activated T cells
CD152 (OX40)	Negative regulator of T-cell activation that interacts with CD80 and CD86 (CTLA4); CD154 costimulator of B-cell activation found on activated T cells
CD158	Stimulatory/inhibitory receptor (KIR) found on NK cells
CD161	Costimulatory receptor found on NK cells and some T cells

Appendix 2.2: Cytokines

Inflammatory cytokines
IL-1α, β	Pluripotent inflammatory cytokine; induce T-cell and macrophage activation and increase body temperature
TNF-α	Tumor necrosis factor-α: induces local inflammation, activation of macrophages, and nitric oxide production; influences metabolism
IFN-α, -β	Interferons-α and -β: type 1 interferons important in antiviral immunity; stimulate NK, stimulate MHC class I expression, and inhibit viral replication
IFN-γ	Interferon-γ: stimulates Th1 cell, NK cell, and macrophage activation and MHC expression by APCs; inhibits Th2 cell differentiation
IL-6	Inflammatory cytokine; stimulates acute phase protein production by the liver and leukocyte production in the bone marrow
IL-8	Chemotactic factor for neutrophils
IL-12	Activates NK and NKT cells and promotes Th1 cell differentiation
IL-17	Important cytokine for mediating the inflammatory process; acts through receptors expressed by many cell types
IL-18	Promotes Th1 cell differentiation
IL-22	Promotes tissue regeneration and repair
Th1 cytokines
IL-2	Stimulates T-cell growth and proliferation and cytotoxicity by NK cells
TNF-β	Tumor necrosis factor-β: important regulatory cytokine; mediates cell killing; also has other metabolic effects
IFN-γ	Interferon-γ: stimulates Th1 cell, NK cell, and macrophage activation and MHC expression by APCs; inhibits Th2 cell differentiation
Th2 cytokines
IL-4	Stimulates production and class switching of IgG1 and IgE and growth of mast cells
IL-5	Stimulates IgA production and growth of eosinophils
IL-6	Stimulates lymphocyte growth and acute phase protein production by the liver
IL-9	Enhances mast cell activity
IL-10	Suppresses Th1 cell and macrophage activity and costimulates mast cell growth
IL-13	Stimulates B-cell growth and differentiation and inhibits macrophage activity
Tr1 cytokines
IL-10	Suppresses Th1 cell and macrophage activity and costimulates mast cell growth
TGF-β	Transforming growth factor-β: inhibits Th1 cells
Hematopoietic growth factors
IL-3	Growth factor for hematopoietic progenitor cells
G-CSF	Granulocyte-colony-stimulating factor: stimulates proliferation and differentiation of cells in the bone marrow to granulocytes
GM-CSF	Granulocyte–macrophage colony-stimulating factor: stimulates growth and differentiation of myeloid cells
IL-7	Induces lymphocyte differentiation, induces RAG1 and RAG2 expression, which is required for TCR and Ig gene rearrangement
IL-15	Induces differentiation of NK and NKT cells

Glossary

Accessory cell

 A cell that aids an adaptive immune response but does not mediate specific antigen recognition

Acute phase proteins

 Series of blood proteins produced by hepatocytes in response to inflammatory cytokines that participate in the early phases of host defense against infection

Adaptive immune response

 The response of antigen-specific lymphocytes to antigen and the development of immunological memory

Adhesion molecules

 Mediate the binding of one cell to another

Adjuvant

 A substance that enhances the immune response to an antigen with which it is mixed

Alleles

 Variants of a single gene

Allergy

 An immune response to an innocuous antigen

Alloreactivity

 The stimulation of T cells by nonself-MHC molecules; can only occur in vitro or during transplantation

Anergy

 A state of T-cell non-responsiveness to antigen and antibody plasma proteins (immunoglobulins) that bind specifically to antigens and mediate neutralization, opsonization, and complement activation

Antibodies

 Antigen-specific receptors found on the surfaces of B cells or secreted by plasma cells; heterodimers (two heavy and two light chains); 5 classes IgM, IgG, IgA, IgD, and IgE

Antigen

 Molecule (usually peptide) recognized by T-cell or B-cell antigen receptor

Antigen presentation

 The display of peptide fragments of protein antigens bound to MHC molecules for T-cell recognition

Antigen-presenting cells (APCs)

 Specialized cells that can internalize, process, and present antigens to T cells, e.g., DCs, some macrophage populations; B cells

Antigen processing

 The intracellular degradation of proteins into peptides for inclusion into MHC class I and MHC class II molecules for presentation to T cells

APC

 See antigen-presenting cell

Apoptosis

 Programmed cell death

Autoimmune disease

 Pathology caused by immune responses to self-antigens

Basophils

 Granulocytes; white blood cells with functions similar to those of mast cells

B cells

 Lymphocytes with antigen-specific immunoglobulin receptors; B7, see CD80 and CD86 (Appendix 2.1)

Bone marrow

 The site of hematopoiesis

CD

 Cluster of differentiation (see Appendix 2.1)

Cell-mediated immunity

 Immune responses involving immune cells, e.g., T cells and NK cells

Chemokines

 Small peptides with conserved cystines that bind to specific receptors and influence white cell trafficking; chemokines direct monocytes, DCs, granulocytes, and lymphocytes bearing the appropriate chemokine receptors to sites of inflammation, infection, or metastasis

Clonal expansion

 Proliferation of antigen-specific lymphocytes, allowing rare cells to increase in number

Complement

 Set of plasma proteins that function in a protein cascade leading to the formation of a lytic complex and production of chemotactic factors and anaphylotoxins

Complement receptors

 Cell-surface receptors that bind pathogen-bound complement, resulting in their phagocytosis

Complementarity-determining regions

 Regions of the T-cell receptor or immunoglobulin molecules that make contact with antigens

Co-receptor

 Cell-surface proteins found on T lymphocytes that have ligands on antigen-presenting cells required for additional signaling necessary for effective T-cell activation

Co-stimulation

 A signal from an APC required in addition to antigen for full activation of lymphocytes

C-reactive protein

 An acute phase protein that binds to phosphatidylcholine on bacteria and opsonises them for phagocytosis

C gene segment

 Constant gene segment, coded for by Ig and TCR genes

CTLA-4, see CD152 (Appendix 2.1)

 Cytokine proteins secreted by cells that affect the behavior of other cells (see Appendix 2.2)

Cytokine receptors

 Cellular receptors for cytokines, cytotoxic T cells, T cells that can kill other cells

D gene segment

 Diversity gene segment, coded for by Ig and TCR genes

Damage-associated molecular patterns (DAMPs)

 Molecules released by stressed or damaged cells undergoing necrosis that act as danger signals to promote or exacerbate the inflammatory response

DC, see dendritic cell

 Dendritic cell; cells of the innate immune system that capture antigens and present them to T cells and direct T-cell subtype differentiation

Diapedesis

 Movement of cells from blood across blood vessel walls into tissues

Digest

 (Context) targeted destruction of engulfed particles or cells by phagocytes

Effector cells

 Lymphocytes that mediate the removal of pathogens from the body without the need for further differentiation

ELISA

 See enzyme-linked immunosorbent assay

ELISpot assay

 An adaptation of ELISA in which individual cells are placed over a bound antibody or antigen that trap the cells’ secreted products and are detected with an enzyme-coupled antibody

Endotoxin

 A bacterial toxin that is released when the cell is damaged

Enzyme-linked immunosorbent assay (ELISA)

 Serological assay in which bound antigen or antibody is detected by a linked enzyme that converts a colorless substrate to a colored product

Eosinophil

 Granulocyte; white blood cell of myeloid lineage involved in immunity against parasites

Epitope

 The region on an antigen that is recognized by a lymphocyte antigen receptor

Fas

 See CD95 (Appendix 2.1)

Fc receptors

 Cellular receptors for the constant portions of immunoglobulins; mediate their biological function

Flow cytometry

 Automated characterization of cells in single cell suspensions with regard to cell size, cell granularity, and fluorescence owing to bound fluorescent antibodies

Gamma-delta (γδ) T cells

 Potent innate effector lymphocytes involved in antitumor immune surveillance

Gene segments

 Segments of TCR and immunoglobulin genes that undergo somatic recombination resulting in the generation of diversity of antigen recognition molecules

Germinal centers

 Sites in secondary lymphoid tissues of B-cell proliferation, selection, and maturation

Granulocytes

 See polymorphonuclear leukocytes

Haplotype

 Set of genes associated with one haploid genome

Granzyme

 A type of serine protease released from granules by CD8⁺ T cells and NK cells that induces death

Helper T cells

 CD4⁺ T lymphocytes

Hematopoiesis

 Generation of all blood cells from their precursors

Histamine

 A vasoactive amine stored in mast cell granules that is released upon antigen binding to IgE molecules on mast cells

Histocompatibility

 The ability of tissues to coexist without eliciting immune responses; HLA (human leukocyte antigens) encoded by the MHC (major histocompatibility complex)

Humoral immunity

 Soluble immune-related molecules, mostly found in the serum, e.g., acute phase proteins, antibodies

Hypersensitivity

 Immune responses to innocuous antigens that occur repetitively; mediated by IgE

ICOS (inducible costimulatory receptors)

 Molecules found on the surface of T cells required for T-cell activation after engagement of the TCR

Ig

 See immunoglobulin

Immunization

 The deliberate provocation of an immune response by introducing antigen

Immunoblotting

 A technique in which proteins are separated by electrophoresis and detected by antibodies

Immunofluorescence

 A technique for detecting molecules in tissue sections using antibodies labeled with fluorescent dyes

Immunoglobulin (Ig)

 Antigen-specific receptors found on the surfaces of B cells or secreted by plasma cells; heterodimers (two heavy and two light chains); 5 classes IgM, IgG, IgA, IgD, and IgE (see antibodies)

Immunoglobulin superfamily

 Proteins with domains that have the sequence and structural features that characterize immunoglobulins/antibodies; usually cell-surface receptors

Immunohistochemistry

 A technique employing enzyme- labeled or fluorescent antibodies to detect specific molecules in tissue sections

Immunological memory

 The ability of antigen-specific effector T cells and B cells to persist for years

Immunoprecipitation

 Detection of soluble proteins using specific antibodies

Immunoreceptor tyrosine-based activation motifs (ITAMs)

 Tyrosine residues on the cytoplasmic domains of signaling proteins that upon phosphorylation trigger cell activation; important for NK function

Immunoreceptor tyrosine-based inhibitory motifs (ITIMs)

 Similar to ITAMs except they signal inhibition of cellular functions; important for NK cell function

Inflammasome

 Large complex of proteins that activate caspase-1 which is required for cleavage of pro-IL-1 to allow it to be secreted from the cell

Inflammation

 Early phase of an immune response involving the local accumulation of plasma proteins and leukocytes at a site of infection; systemic inflammation is characterized by acute phase protein production

Innate immunity

 A variety of defense mechanisms that non-specifically target pathogens in the early stages of an immune response

Integrins

 A family of adhesion molecules found on the surfaces of immune and endothelial cells

Interferons

 A family of cytokines with antiviral activity

Interleukins

 Cytokines produced by leukocytes (see Appendix 2.2)

J chain

 Protein used to hold the pentamer of IgM and the dimer of IgA together, coded for by a non-immunoglobulin gene

J segment

 Joining gene segment, found amongst Ig and TCR gene segments

Knockout mice

 Mice with heritable targeted disruptions of specific genes

Kupffer cell

 Specialized macrophages (phagocytic cells) in the liver

Langerhans cells

 Macrophages found in the skin

Leukocyte

 General term for white blood cells

Lymphatic system

 A series of vessels that drain fluid from the tissues to the blood, carrying lymphocytes and other immune cells and molecules

Lymph nodes

 Secondary lymphoid organs where adaptive immune responses are initiated

Lymphocytes

 Mononuclear leukocytes that mediate adaptive immune responses; include T and B lymphocytes and natural killer cells

Lymphokines

 Cytokines produced by lymphocytes

Macrophage

 Myeloid cell of the innate immune system with APC function found in the tissues (e.g., Langerhans cells in the skin; Kupffer cells in the liver)

Major histocompatibility complex (MHC)

 Highly polymorphic gene complex found on chromosome 6 in the human; codes for class I and class II antigen-presenting molecules as well as other molecules of immunological importance

Mannose binding lectin

 Acute phase protein synthesized in the liver early in inflammation

Mast cells

 Histamine-releasing cells of myeloid origin with IgE receptors found fixed in tissues

Membrane attack complex

 Complement components that can disrupt membranes of pathogens

MHC

 See major histocompatibility complex

MHC restriction

 Recognition of peptide antigens presented by MHC molecules by T cells

MICA, MICB

 MHC class I-related stress proteins expressed by epithelial cells recognized by NK cells and some T cells

Minor histocompatibility antigens

 Antigens that can lead to graft rejection when recognized by T cells

Minor lymphocyte stimulatory (Mls) loci

 Mammary tumor virus genes integrated into the mouse genome that code for superantigens

MIP-1α and -β

 Macrophage inflammatory proteins α and β chemokines

Monoclonal antibodies (MAbs)

 Antibodies produced by a single clone of B cells

Monocyte

 Myeloid phagocytic cell found in the circulation

Myeloid cells

 Macrophages and granulocytes

Myeloid-derived suppressor cells

 Cells of the myeloid lineage capable of suppressing T-cell activity by secreting IL-10 and TGF-β

N nucleotides

 Extra nucleotides that are inserted into the junctions between gene segments of TCR and Ig DNA, by terminal deoxynucelotidyl transferase (Tdt) to create further diversity

Naïve lymphocytes

 Lymphocytes that have never encountered antigen

Natural cytotoxicity

 Spontaneous killing of cells by NK cells

Natural killer (NK) cells

 Lymphoid cells of the innate immune system that kill virus-infected and tumor cells

Natural killer T (NKT) cells

 Cells that combine the phenotypic and functional characteristics of NK cells and T cells

Necrosis

 Death of cells owing to physical or chemical injury, as opposed to apoptosis

Negative selection

 Intrathymic deletion of developing T cells that recognize self-antigens

Neutralization

 Inhibition of infectivity of a virus or toxicity of a toxin by antibodies

Neutrophil

 Polymorphonuclear, phagocytic leuckocyte; most numerous in the circulation

NK cell

 See natural killer cell

NK1.1+ T cell

 T cells that express the NK cell stimulatory receptor NK1.1

NKG2D

 Activating receptor found on NK cells and some T cells

Kp46

 Natural cytotoxicity receptor found on NK cells that recognizes viral hemagglutinin

NKT cells

 See natural killer T cells

NOD-like receptors (NLRs, NODs)

 Family of intracellular PRRs that recognize cytoplasmic PAMPs

Nude mice

 A mutant strain of mice with no hair and defective thymic formation so they have no mature T cells

Opsonization

 Alteration of the surface of a pathogen, e.g., due to binding of acute phase proteins, so that it can be recognized and ingested by phagocytes

Pathogen-associated molecular patterns (PAMPs)

Conserved antigenic structures present on microorganisms that are recognized by the innate immune system

Pattern recognition receptors (PRRs)

 Receptors on cells of the innate immune system that recognize common structures (PAMPs) found on infectious agents

Perforin

 A protein produced by T cells and NK cells that can polymerize to form a pore in a target cell as part of cell killing

Peyer’s patches

 Aggregates of lymphocytes in the small intestine

Phagocytic cell

 Cells of the myeloid lineage that have the ability to engulf particles and cells

Phagocytosis

 Engulfment of particles, microbes, and dying cells by cells of the myeloid lineage

Plasma cell

 A terminally differentiated B cell capable of producing antibodies

Polygenic

 Several gene loci code for multiple proteins of similar function

Polymerase chain reaction (PCR)

 A technique for amplifying specific sequences of DNA

Polymorphic

 A gene locus with multiple alleles

Polymorphonuclear leukocytes

 White cells of myeloid lineage, characterized by their granules and the shape of their nuclei with potent phagocytic and microbial killing potential; see neutrophils, basophils, eosinophils

Positive selection

 Selective maturation of T cells that can recognize self-MHC molecules in the thymus

Priming

 Initial interaction between a lymphocyte and an antigen

Professional APC

 Cells that are capable of presenting antigen to naïve T cells

Programmed death receptor-1 (PD-1)

 A receptor on activated lymphocytes that mediates inhibition of lymphocyte effector functions

Proteosome

 A multifunctional protease that degrades antigenic proteins into peptides for antigen presentation

Radioimmunoassay (RIA)

 A technique in which an antigen or antibody is bound to a solid support and specific radiolabeled antibody or antigen in a preparation is quantified by binding to these molecules

RAG1 and RAG2

 Recombinase activating gene products required for TCR and Ig gene rearrangement

RANTES (Regulated on Activation, Normal, T-Cell Expressed and Secreted)

 A chemokine responsible for influencing the migration of T lymphocytes

Receptor-mediated endocytosis

 Internalization of molecules by cells using specific receptors for the molecules

Receptor repertoire

 The totality of lymphocyte receptors present in an individual

Regulatory T cells (Tr cells)

 T cells that suppress the activity of effector T cells through secretion of IL-10 and/or TGF-β

Respiratory burst (oxidative burst)

 Following phagocytosis, the sharp increase in the uptake of oxygen, which facilitates the production of superoxide and hydrogen peroxide, potent killers of microbes

RIG-I-like receptors

 Family of RNA helicase enzymes that specifically recognize viral derived RNA in the cytoplasm

Secondary immune response

 The more rapid, potent, and specific lymphocyte response elicited by second exposure to antigen, characterized by higher affinity antibodies of the IgG class

Second signal

 A costimulatory signal required for lymphocyte activation

Selectins

 A family of adhesion molecules

Sero-conversion

 The phase of an infection during which antibodies are produced

Serology

 The use of antibodies to identify antigens

Somatic recombination

 Rearrangement of TCR or Ig gene segments

Superantigens

 Molecules that stimulate whole families of T cells by binding to MHC class II molecules and Vβ domains of the TCR

Suppressor T cells

 See T regulatory cells

Syngeneic

 Between two genetically identical individuals; T-cell lymphocytes that mature in the thymus and recognize antigen by a TCR associated with the CD3 protein complex

T-cell clone

 Cultured T cells expanded from a single cell

T-cell line

 Cultures of T cells grown by repeated stimulation

T-cell receptor (TCR)

 Antigen-specific receptors on T cells

Terminal deoxynucleotidyl transferase (Tdt)

 Enzyme which inserts extra nucleotides into the junctions between gene segments of TCR and Ig DNA, to create further diversity; also used in TUNEL, assay for apoptosis

T lymphocyte

 See T cell

TCR

 See T-cell receptor

TGF-β

 See Appendix 2.2

Th1 cells

 CD4⁺ T cells that secrete IFN-γ, TNF-β, and IL-2, activate macrophages, and promote inflammation

Th2 cells

 CD4⁺ T cells that secrete IL-4, -5, -9, -10, and -13 and promote B-cell differentiation

Th3 cells

 T regulatory cells; CD4⁺ T cells that secrete TGF-β and or IL-10 and suppress Th1 cell responses

Th17 cells

 CD4⁺ T cells that secrete IL-17, -17F, -21, and -22; important during inflammation

Thymus

 Organ where T cells differentiate from bone marrow-derived lymphoid progenitor cells and undergo positive and negative

TNF (tumor necrosis factor)

 An inflammatory cytokine (see Appendix 2.2)

Tolerance

 The failure of the immune system to respond to antigen

Toll-like receptors

 Receptors on macrophages and dendritic cells that recognize common components of microorganisms and mediate signaling pathways (analogous to the Toll receptor in Drosophila)

Transgene

 Introduction of foreign genes to the genome of an organism

T regulatory cells

 CD4⁺ T cells that secrete TGF-β and or IL-10 and suppress T-cell responses; can be inducible or constitutive

V gene segments

 Variable gene segment, coded for by Ig and TCR genes

Vaccination

 The deliberate induction of immunity against a pathogen by immunization with a dead, attenuated, or defective form of the pathogen

Western blotting

 A technique for detecting proteins separated by gel electrophoresis using labeled antibodies

Xenogeneic

 Immune response elicited between organisms of different species