MLSC 3031 - Clinical Immunology I - Chapter/Module 4 – Antigen Recognition in the Adaptive Immune System: Structure of Lymphocyte Antigen Receptors and Development of Immune Repertoires

B cells

Cells that signal transduction by Ig-alpha and Ig-beta (co-expressed)

T cells

cells that receive signal transduction by CD3 and zeta chain for activation

B cell effector functions

constant regions of secreted immunoglobulin

T cells

these cells don't have any TCR effector functions because they aren't secreted

Effector functions of antibodies (secreted BCRs)

Neutralization of microbes and toxins
Opsonization and phagocytosis of microbes
Antibody-dependent cellular toxicity
Phagocytosis of microbes opsonized with complement fragments (e.g., C3b)
Inflammation
Lysis of microbes
Complement activation

General structure of antibodies

2 identical light chains and 2 identical heavy chains held together by disulfide bonds

Heavy chains

composed of 1 variable region (V) and 3 constant regions (C); there are 5 types: μ, δ, γ, ε, and α

Light chains

composed of 1 variable region and 1 constant region; there are 2 types: κ and λ

CDRs

hypervariable regions of the variable regions; variable regions of antigen binding

Three

amount of CDRs (complementarity-determining regions) in each variable region

Fab region

fragment antigen binding region of the antibody

Fc region

fragment, crystalline region of the antibody

IgG

secreted immunoglobulin

IgM

first antibody produced; bound immunoglobulin

IgM

immunoglobulin that has 4 constant regions instead of the 3 seen on the heavy chains of IgG; has additional residues at the C termini which codes for the transmembrane domain of the molecule

J chain

binds antibody isotypes (IgA, IgD, etc.) together

IgA

antibody isotype that is mainly dimer, also monomer, trimer; function is mucosal immunity

IgD

antibody isotype that is not secreted, is a monomer, and function is naive B cell antigen receptor

IgE

antibody isotype that has a short serum half-life due to hypersensitivity reactions, is a monomer, and functions are defense against helminthic parasites and immediate hypersensitivity

IgG

antibody isotype that has the highest serum concentration, last the longest in circulation, is monomer, and functions are:
- opsonization
- complement activation
- antibody-dependent cell-mediated cytotoxicity
- neonatal immunity
- feedback inhibition of B cells

IgM

antibody isotype that is a pentamer, has an extra constant domain, the Fc is not accessible so it works in conjunction with IgG, and its functions are naive B cell antigen receptor (monomeric form), and complement activation

IgG, IgM

the only 2 isotypes that can activate complement (classical pathway)

Epitope (determinant)

the part of the antigen that the host's immune system recognizes; binds to the CDRs of each Fab arm

Affinity

the strength of binding antigen and antibody on the Fab binding site

Affinity maturation

hypermutation of the genetic sequence of the CDRs leads to higher affinity

Avidity

the total strength of antibody binding to antigen, which includes the "valence", or how many antigens can an antibody bind (IgG has 2 binding sites, IgM is bivalent and has 5 binding sites (10 in total), so it has a higher sum of interactions)

Cross-reactivity

the ability of antibodies to bind an antigen that is different (but structurally similar) to the antigen to which they were initially raised to react against

Class switching

ability of a B cell to produce a different class of antibody against one antigen; at the end of its maturation, B cells can decide to switch it's heavy chain expression from IgM or IgG to another immunoglobulin; also known as isotype switching

Hybridoma

a hybrid cell used to generate monoclonal antibodies that results from the fusion of human myeloma cell + mouse spleen cell (B cell)

Monoclonal antibodies

Antibodies made from cells that are cloned from one cell

T cell and B cell

Cell receptors that are cell/membrane-bound

Variable

region of B cell receptors and T cell receptors that recognize antigens; N terminal region of an Ig Heavy or light chain or a TCR α, β, γ, or δ chain

T cell (TCR) subpopulations

gamma/delta T cells, NK-like T cells, MAIT (mucosal associated invariant T) cells; functions are not well understood for these groups of lymphocytes!

Gamma/Delta T cells

T cell subpopulation that:
- Express receptors composed of gamma (γ) and delta (δ) chains
- Recognize a variety of antigens, usually not displayed by classical MHC molecules
- Abundant in epithelia, perhaps to recognize microbes
- About 5% to 10% of T cells in the body

NK-like T cells

T cell subpopulation that:
- Express αβ TCRs with limited diversity and NK cell surface molecules
- Recognize lipid antigens displayed by class I MHC-like molecules called CD1
- Comprise less than 5% of all T cells

MAIT (mucosal associated invariant T) cells

T cell subpopulation that:
- Express αβ TCRs with limited diversity
- Approximately 5% of blood T cells, but up to 20%-40% of human liver T cells

TCR structure

- Heterodimer, composed of alpha chain and beta chain
- Variable (N-terminal) and constant (C-terminal) region
- Each variable region has three CDRs (total of six for the molecule - 3 on the alpha chain, 3 on the beta chain)
- CD3 and zeta chain are involved in signal transduction

Yes

Do B cells class switch (change constant region to other immunoglobulins)?

No

Do T cells class switch?

Yes

Do B cells have affinity maturation?

No

Do T cells have affinity maturation?

V, D (diversity), J (joining) genes

heavy chain gene locus and TCR-beta gene locus have these genes that make up the entire variable region

V and J genes

light chain genes and TCR-alpha genes have these gene segments for their variable region

Combinatorial diversity

the diversity of Ig and TCR specialities generated by the use of many different combinations of different variable, diversity, and joining segments during somatic recombination of DNA in the Ig and TCR loci in developing B and T cells; limited by the number of gene segments and possible combinations; works with junctional diversity

Junctional diversity

the diversity in antibody and TCR repertoires that is created by the random addition or removal of nucleotide sequences at junctions between V, D, and J gene segments; unlimited possibilities

IgM

pre-B cells express cytoplasmic _____ heavy chain protein

IgM

immature B cells express surface ___

IgM, IgD

mature (but naive) B cells express surface _____ and _____

Allelic exclusion

B cells exhibit this, i.e., both immunoglobulin alleles cannot express their protein in the same cell, thus cells only make one light chain; only one heavy chain and one light chain are produced in each B-cell

Receptor editing

when a B cell makes a strongly self-reactive antibody, they can re-activate its recombination mechanism to change its antibody; can occur multiple times

Positive selection (of T cells)

The process by which developing T cells in the thymus (thymocytes) whose TCRs bind to self MHC molecules are rescued from programmed cell death, whereas thymocytes whose receptors do not recognize self MHC molecules die by default. Ensures that mature T cells are self MHC restricted and that CD8+ T cells are specific for complexes of peptides with class I MHC molecules and CD4+ T cells for complexes of peptides with class II MHC molecules.

Negative selection (of T cells)

The process by which developing T lymphocytes that express self-reactive antigen receptors are eliminated, thereby contributing to the maintenance of self tolerance.

Apoptosis

fate of T cells that cannot see self-MHC

CD8+ cells

fate of T cells that recognize Class I MHC molecules

CD4+ cells

fate of T cells that recognize Class II MHC molecules

Negative selection

fate of cells that strongly react to self peptides

V(D)J Recombination

a process by which the genes responsible for encoding the variable region of the B-cell receptor and T-cell receptor are rearranged to create a diverse repertoire of receptors capable of recognizing a wide variety of antigens; DNA segments called V (variable), D (diversity), and J (joining) are rearranged to form the coding sequence for the receptor variable region. The process is mediated by recombination-activating genes (RAG1 and RAG2) and involves the introduction of double-strand breaks at specific recombination signal sequences (RSS) flanking the V, D, and J segments, followed by joining of the broken ends