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B-cell antigen recognition

B cells use BCRs to recognize native antigen directly without requiring MHC presentation

T-cell antigen recognition

T cells use TCRs to recognize peptide antigen presented by self-MHC

MHC restriction

TCR recognition requires an antigenic peptide presented by an appropriate self-MHC molecule

Antigens recognized by B cells

B cells can recognize proteins polysaccharides lipids nucleic acids and small chemicals

Antigens recognized by T cells

Conventional T cells primarily recognize protein-derived peptides presented by MHC

BCR

B-cell receptor that directly binds antigen and determines antigen specificity

TCR

T-cell receptor that recognizes peptide-MHC complexes

BCR signaling molecules

Igα and Igβ contain ITAMs and transmit signals from the BCR

TCR signaling molecules

CD3 and ζ chains contain ITAMs and transmit signals from the TCR

ITAM

Immunoreceptor tyrosine-based activation motif that initiates intracellular signaling after phosphorylation

Clonal proliferation

Expansion of an activated antigen-specific lymphocyte into many cells with the same specificity

Why clonal proliferation is necessary

Rare antigen-specific lymphocytes must expand to generate enough cells for an effective response

Clonal selection

Antigen selects lymphocytes with preexisting receptors capable of recognizing that antigen

Preexisting lymphocyte repertoire

A diverse collection of lymphocyte specificities generated before antigen exposure

V(D)J recombination

DNA rearrangement that generates unique antigen-receptor variable-region genes before antigen exposure

Heavy-chain V(D)J rearrangement

Heavy-chain variable regions are produced by joining V D and J gene segments

Light-chain V(D)J rearrangement

Light-chain variable regions are produced by joining V and J gene segments

Combinatorial diversity

Diversity produced by different combinations of V D and J gene segments and receptor-chain pairing

Junctional diversity

Diversity produced by nucleotide addition and removal at V D and J junctions

RAG1 and RAG2

Proteins that recognize RSSs and initiate DNA cleavage during V(D)J recombination

RSS

Recombination signal sequence that marks antigen-receptor gene segments for RAG-mediated rearrangement

12-23 rule

A gene segment with a 12-spacer RSS normally recombines with one carrying a 23-spacer RSS

Purpose of the 12-23 rule

Ensures appropriate V D and J gene segments are joined during receptor rearrangement

TdT

Enzyme that randomly adds non-templated N nucleotides at V(D)J junctions

TdT and receptor diversity

TdT increases junctional diversity by adding random nucleotides at gene-segment junctions

Single lymphocyte specificity

Each lymphocyte expresses many copies of essentially one antigen-receptor specificity

Allelic exclusion

Mechanism that helps ensure one B cell expresses one functional heavy-chain and light-chain specificity

Pro-B cell

B-cell developmental stage in which heavy-chain rearrangement occurs

Heavy-chain rearrangement sequence

D-to-J joining occurs first followed by V-to-DJ joining

Pre-B cell

B-cell stage that has successfully produced a functional mu heavy chain

Pre-BCR

Functional mu heavy chain paired with surrogate light chain and signaling molecules

Surrogate light chain

VpreB and lambda5 proteins that temporarily pair with the mu heavy chain

Purpose of the pre-BCR

Tests whether the newly rearranged heavy chain can form a functional receptor

Pre-BCR and allelic exclusion

Successful pre-BCR signaling stops further heavy-chain rearrangement

Pre-BCR and proliferation

Successful pre-BCR signaling stimulates several rounds of pre-B-cell division

Pre-BCR and light-chain rearrangement

Successful pre-BCR signaling initiates light-chain rearrangement

Light-chain rearrangement

V-to-J recombination produces a functional kappa or lambda light chain

Immature B cell

B cell expressing a complete surface IgM BCR

Functional BCR checkpoint

Successful heavy and light chain expression produces surface IgM and allows further development

B-cell self-tolerance

Developing B cells are tested for self-reactivity before completing maturation

Receptor editing

Additional light-chain rearrangement that can replace a strongly self-reactive BCR

Clonal deletion

Apoptotic elimination of strongly self-reactive B cells

Anergy

Functional unresponsiveness of a self-reactive B cell

B-cell developmental sequence

Pro-B to pre-B to immature B to transitional B to mature naïve B cell

Site of early B-cell development

Bone marrow

Site of final B-cell maturation

Spleen

Transitional B cell

Immature B cell that has left bone marrow and is completing maturation in the spleen

Mature naïve B cell

Mature antigen-inexperienced B cell that coexpresses surface IgM and IgD

IgM and IgD coexpression

Differential RNA processing allows the same mature naïve B cell to produce both IgM and IgD

IgM and IgD antigen specificity

IgM and IgD on the same B cell have the same variable region and antigen specificity

IgM to IgD expression

Occurs by differential RNA processing rather than class-switch recombination

B1 B-cell development

B1 cells primarily develop from fetal liver-derived hematopoietic stem cells

B1 B-cell BCR diversity

B1 cells have limited BCR diversity biased toward common polysaccharides and lipids

B1 B-cell isotype

B1 cells mainly produce natural IgM

B1 B-cell location

B1 cells are found mainly in peritoneal and mucosal sites

B1 B-cell function

B1 cells provide rapid broad protection through natural antibodies

Marginal-zone B2 development

Marginal-zone B2 cells develop from bone marrow-derived hematopoietic stem cells

Marginal-zone B2 diversity

Marginal-zone B2 cells have relatively limited BCR diversity similar to B1 cells

Marginal-zone B2 location

Marginal-zone B2 cells reside in the marginal zone of the spleen

Marginal-zone B2 isotype

Marginal-zone responses primarily produce IgM

Marginal-zone B2 function

They rapidly respond to blood-borne pathogens and often generate short-lived plasma cells

Follicular B2 development

Follicular B2 cells develop from bone marrow-derived hematopoietic stem cells and mature in spleen

Follicular B2 diversity

Follicular B2 cells possess a highly diverse BCR repertoire

Follicular B2 isotypes

Mature naïve follicular B cells coexpress surface IgM and IgD

Follicular B2 location

Follicular B2 cells recirculate through B-cell follicles of secondary lymphoid organs

Follicular B2 function

Follicular B2 cells mediate T-dependent responses including class switching and affinity maturation

Antibody basic structure

An antibody monomer contains two identical heavy chains and two identical light chains

Heavy chain

Antibody chain that contributes to antigen binding and whose constant region determines isotype

Light chain

Antibody chain that combines with the heavy-chain variable region to form the antigen-binding site

Variable region

Region of heavy and light chains responsible for antigen specificity

Constant region

Region responsible for antibody structural and effector properties

Antigen-binding site

Site formed by the variable regions of one heavy and one light chain

Hinge region

Flexible region that allows antibody arms to bind epitopes separated by different distances

Fab

Antibody region responsible primarily for antigen binding

Fc

Antibody region that binds Fc receptors and complement to initiate effector functions

Neutralization

Antibody blocks pathogens or toxins from interacting with host-cell receptors

Opsonization

Antibody coats a pathogen and promotes Fc receptor-mediated phagocytosis

Complement activation

Antigen-bound IgM or IgG activates the classical complement pathway

ADCC

Antibody-coated targets are killed by Fc receptor-bearing innate immune cells

Agglutination

Antibodies cross-link particulate antigens to form clumps that facilitate elimination

Mast-cell and basophil activation

Antigen cross-links receptor-bound IgE and triggers degranulation

Antibodies and innate immunity

Antibodies provide antigen specificity while Fc regions recruit innate cells and complement

IgM structure

Secreted IgM is primarily a pentamer joined by a J chain

IgM location

Secreted IgM is found mainly in blood

IgM timing

IgM is the first antibody secreted during a primary immune response

IgM functions

IgM efficiently activates complement promotes agglutination and can neutralize antigen

IgG structure

IgG is a monomer

IgG location

IgG is abundant in blood and tissues and can cross the placenta

IgG timing

IgG appears later in primary responses and predominates in blood during secondary responses

IgG functions

IgG mediates opsonization neutralization ADCC complement activation and passive fetal protection

IgA structure

IgA is mainly monomeric in blood and dimeric with a J chain in secretions

IgA location

Secretory IgA predominates at mucosal surfaces and in secretions

IgA functions

IgA neutralizes pathogens and prevents microbial adherence and colonization at mucosal surfaces

IgE structure

IgE is a monomer

IgE location

IgE is primarily bound to Fc receptors on tissue mast cells and basophils

IgE functions

IgE mediates mast-cell degranulation and defense against helminths

IgD structure

IgD is a monomer

IgD location

IgD is primarily expressed as a BCR on mature naïve B cells

IgD function

IgD functions primarily as an antigen receptor on mature naïve B cells

Fc receptor

Receptor that binds an antibody Fc region and connects antibody recognition to localization or effector function