Adaptive Immune Response 8/25

types of adaptive immunity

humoral and cell-based (cellular)

role of humoral immunity

use antibodies released by B lymphocytes to neutralize/eliminate microbes

role of cellular immunity

use T lymphocytes/effector T cells to regulate immune responses (CD4+ helper T cells) and kill target cells such as virus-infected cells (CD8+ cytotoxic T cells)

antigen

a molecule that could be recognized by lymphocytes (B cells and T cells) or antibodies

immunogens

antigens that are capable of inducing an immune response in the host organism

antigen-presenting cells (APCs)

cells that capture microbial antigens and display them for recognition by T lymphocytes

APC expression

express major histocompatibility complex (MHC molecules);

the majority of T lymphocytes recognize peptide antigens that are bound to and displayed by MHC molecules on APCs

professional APCs

dendritic cells, macrophages, B cells

dendritic cells (DCs)

the most efficient and specialized APCs

macrophages

APCs that engulf microbes and display the microbial antigens to T cells

B cells

APCs that ingest protein antigens and display to helper T cells which enhances antibody secretion

non-professional APCs

all nucleated cells can present antigens to T cells

capture of protein antigens by APC

DCs are present in tissues in contact with external environment so microbes that breach the epithelial barriers and enter the body are captured mainly by DCs

4 step process of capture and display of microbial agents by APC

1. capture antigens (phagocytosis/endocytosis)

2. activation of DC (initiate inflammation and innate immunity)

3. migration of antigen-carrying DC to lymph nodes

4. display antigen to T cells (APC/adaptive immunity)

major histocompatibility complex (MHC)

molecules that are membrane proteins expressed on APCs that display peptide antigens for recognition by T lymphocytes

MHC location

found in all mammals

human MHC proteins

human leukocyte antigens (HLA) that cause rejection after transplantation

MHC locus

contains two sets of highly polymorphic genes (class I and II) and many non-polymorphic genes (class III)

MHC restriction

T lymphocytes of a specific individual can see peptides only when these peptides are displayed by that individual's MHC molecules; one's T cells can only recognize peptide antigens presented by one's own MHC on APC

MHC gene locus

located on chromosome 6; class I and II regions are polymorphic (on each end) and class III region is non-polymorphic (in the middle)

properties of MHC genes

highly polymorphic and codominantly expressed

highly polymorphic nature of MHC genes

many different alleles (10,000 class I MHC alleles and 3000 class II MHC alleles) are present in the populations of human beings

inherited not generated de novo by somatic gene recombination

ensures different individuals are able to present and respond to different microbial peptides

codominant expression of MHC genes

both parental alleles are expressed which increases the number of different MHC molecules that can present peptides to T cells

expression of class I MHC molecules

all nucleated cells (APCs); CD8+ CTLs can kill any type of virus-infected cell

expression of class II MHC molecules

professional APCs (DCs, macrophages, and B lymphocytes); CD4+ helper T lymphocytes interact with dendritic cells, macrophages, and B lymphocytes

class I MHC molecule characteristics

composed of 8-9 amino acids

a1 and a2 domains form peptide-binding cleft and are highly variant (polymorphic)/different among different individuals

a3 domain is invariant/binds coreceptor (CD8) on CD8+ T cells (cytotoxic T cells)

class II MHC molecule characteristics

composed of 10-30 amino acids

a1 and a2 domains form peptide-binding cleft

a1 and B1 domains are highly variant

a2 and B2 domains are invariant/bind coreceptor (CD4) on CD4+ T cells (helper T cells)

6 features of peptide binding to MHC

1. broad specificity (many different peptides can bind to the same MHC molecule)

2. each MHC molecule displays one peptide at a time

3. MHC molecules bind only peptides

4. peptides are acquired during intracellular assembly (class I and II MHC molecules display peptides from different cellular compartments)

5. stable surface expression of MHC molecule requires bound peptide

6. very slow off-rate (MHC molecule displays bound peptide for long enough to be located by T cell)

processing and presentation of protein antigens - class I MHCs

cytosol proteins of any nucleated cells are processed in proteolytic structures called proteasomes and displayed by class I MHC molecules

processing and presentation of protein antigens - class II MHCs

extracellular proteins that are internalized by professional APCs are processed in endosomes and lysosomes and displayed by class II MHC molecules

steps of processing and presentation of cytosol proteins

proteolysis of cytosolic proteins, binding of peptide to class I MHC molecules, transport of peptide-MHC complexes to the cell surface

proteolysis of cytosolic proteins

cytosol proteins (intracellular microbes such as viruses) are unfolded, covalently tagged with ubiquitin, and degraded by proteasome peptides

binding of peptide to class I MHC molecules

class I MHC are synthesized in the ER and the transporter associated with antigen processing (TAP) is located in the ER membrane and binds and pumps peptides from cytoplasm to ER

transport of peptide-MHC complexes to the cell surface (MHC-1)

class I MHC bind peptide, become stabilized, and transported to cell surface then recognized by CD8+ T cells; class I MHC empty, unstable, degraded

steps of processing and presentation of extracellular proteins

internalization and digestion of antigens, binding of peptides to class II MHC molecules, transport of peptide-MHC complexes to cell surface

internalization and digestion of antigens

extracellular microbes (such as bacteria and fungi) or microbial proteins are internalized by APCs (phagocytosis or endocytosis), enter endosomes/phagosomes, fuse with lysosomes, and are broken down into peptides

binding of peptides to class II MHC molecules

class II MHC are synthesized in ER, carry invariant chain, and fuse with endosomal vesicle

transport of peptide-MHC complexes to cell surface (MHC-2)

class II MHC bind a peptide, stable, delivered to cell surface, recognized by CD4+ T cells; class II is empty, unstable, degraded

significance of MHC complex-associated antigen presentation

the restriction of T cell recognition to MHC-associated peptides ensures that T cells see and respond only to cell-associated antigens; express on cell membrane and require intracellular biosynthetic and assembly steps

significance of segregating the class I and class II pathways of antigen processing

immune system is able to respond to extracellular and intracellular microbes in different ways that are best able to combat these microbes

class I MHC (CD8+ T cell) antigen processing

all nucleated cells infected by intracellular microbes

class II MHC (CD4+ T cell) antigen processing

macrophages and DCs ingest bacteria and fungi (extracellular microbes) and B cells ingest microbial protein (extracellular microbes)

functions of APCs

display peptides for recognition by T cells ("first signal") and express "second signal" for T cell activation

"first signal" of APCs

APC express MHC-peptide complex and T cells express T cell receptor and CD4/CD*

"second signal" of APCs

APC express B7 and T cells express CD28

types of APCs

class I MHC (all nucleated cells) and class II MHC (DCs, macrophages, B cells)

structure of class I MHC molecules

variant a1 and a2 domains that bind antigen peptides and invariant a3 domain that binds CD8

structure of class II MHC molecules

variant a1 and B1 domains that bind antigen peptides and invariant a2 and B2 domains that bind CD4

properties of peptides binding to MHC molecules

broad specificity, one at a time, only peptides, intracellular assembly machinery, stable when bound to peptides, slow off-rate

processing and presentation of protein antigens in cytosol

class I MHC, CD8+ T cells, kill antigen-expressing target cells

processing and presentation of protein antigens extracellularly

class II MHC, CD4+ T cells, activate macrophages and DCs to kill microbes, help B cells secrete antibodies

types of antigen receptors

B cell receptors (BCR) and T cell receptors (TCR)

features of antigen receptors

BCRs and TCRs recognize chemically different structures, contain different regions, and do not deliver intracellular signals by themselves

chemical structures recognized by BCRs

shapes or conformations of macromolecules including proteins, lipids, carbohydrates, nucleic acid, and small chemical groups, and diverse microbes and toxins in their native forms

chemical structures recognized by TCRs

peptides presented by APCs = cell-associated antigens

regions on BCR/TCR

variable (V) regions that recognize antigens and vary between clones of lymphocytes

constant (C) regions that have structure integrity and effector functions conserved among all clones

BCR/TCR complexes

do not deliver intracellular signals by themselves and are instead associated with invariant molecules that deliver intracellular signals after antigen recognition

antibodies

aka immunoglobulins (Igs) that have two forms - membrane-bound BCR and secreted proteins

membrane-bound BCR antibody form

recognize antigens and initiate the responses

secreted protein antibody form

neutralize and eliminate microbes and their toxins

structure of antibodies

two identical heavy (H) chains that each contains a variable (V) region and 3-4 constant (C) regions and two identical light (L) chains that each contains a variable (V) region and a constant (C) region

Ig domain

a characteristic three-dimensional shape of two layers of a B sheet held together by a disulfide bridge

CDRs (complementarity determining region) role

antigen recognition and binding

binding of antigens by antibodies

antigen-binding site of an antibody is composed of the V regions of both the heavy and light chains and the core antibody structure contains two identical antigen binding sites; each V region contains three hypervariable regions (CDRs)

5 isotypes of antibodies

IgA, IgD, IgE, IgG, IgM

IgA function/secreted form

mucosal immunity; mainly dimer but also monomer and trimer

IgD function/secreted form

naive B cell antigen receptor; monomer

IgE function/secreted form

defense against helminthic parasites and immediate hypersensitivity

monomer

IgG function/secreted form

opsonization, complement activation, antibody-dependent cell-mediated cytotoxicity, neonatal immunity, feedback inhibition of B cells; monomer

IgM function/secreted form

naive B cell antigen receptor (monomeric form), complement activation; pentamer

features of antibodies

five classes (isotopes), differ in C regions, heavy-chain class (isotope) switching, capable of binding a wide variety of antigens (macromolecules and small chemicals), epitopes, affinity, BCR complex

epitopes of antibodies

determinants that are the part of the antigens that are recognized by antibodies; can be sequences of linear epitopes or shapes of conformational epitopes

affinity of antibodies

the strength of antibody binds to one epitope of an antigen

affinity maturation

affinity increases in secondary immune response

BCR complex of antibodies

Ig attach to Iga and IgB that transmit signals to the interior of B cells leading to B cell activation

T cell receptors for antigens structure

membrane-bound heterodimeric protein that contains an a chain (one V and one C region), a B chain (one V and one C region), and CDRs (three hypervariable complementarity-determining regions)

antigen recognition by TCR

the V region of the a and B chains of the TCR participate in specific recognition of antigen peptides displayed by MHC molecules; each TCR recognizes as few as one to three residues of the MHC-associated peptides

TCR complex

TCR, CD3, and zeta proteins that transmit signals; TCR does not transmit signals to T cells

production of diverse antigen receptors

antigen receptor genes are inherited, a collection of diverse BCR/TCR is called lymphocyte repertoires/immune repertoires, diverse antigen receptors are generated through random recombination or junctional diversity

comparison of TLR4, MHC, and BCR receptors

TLR4 is inherited and identical across the population, MHC is inherited as one single expression but there are different types across the population, BCR is inherited and expressed differently in the cell and throughout the population

inherited antigen receptor genes

Ig H/L-chain loci and TCR a/B-chain loci contain 30-45 variable (V) region gene segments, one or a few constant (C) region gene segments, diversity (D) segments (only Ig H-chain and TCR B-chain loci), and joining (J) gene segments

mechanism of V(D)L recombination

random selection of gene segments (random selection or somatic recombination) during B cell development

random/somatic recombination

generation of diverse antigen receptors of gene segments that code for the V regions of BCR/TCR

combinational diversity

different combinations of V, D, and J gene segments

mechanisms of producing junctional diversity

exonucleases may remove nucleotides from V, D, and J; terminal deoxynucleotidyl transferase (TdT) catalyzes the random addition of nucleotides to the junctions between V/D segments and D/J segments; overhanging DNA sequences may be generated

maturation and selection of B cells

stem cell > pro-B > pre-B (pre-BCR and u) > immature B (IgM) > mature B (IgM and IgD)

early steps in B cell maturation

recombination of heavy-chain loci occurs in pre-B cells and pre-B cells express u heavy-chain, surrogate light chains, and Iga and IgB, forming the pre-B cell receptor (pre-BCR) complex

completion of B cell maturation

pre-BCR complex triggers recombination of light chain loci leading to coexpression of IgD and IgM

selection of mature B cells

positive selection (survival) or negative selection (apoptosis)

positive selection of mature B cells

survive - express functional BCR AND do not recognize self-antigens

negative selection of mature B cells

apoptosis - fail to express functional BCR OR recognize self-antigens

outcomes of maturation and selection of B cells

generate a collection of mature B cells that are able to recognize any microbial antigens

maturation and selection of T cells

stem cell > double negative (CD4-CD8-) pro-T cell > pre-T cell > double positive (CD4+CD8+) immature T cell > mature CD4+ or CD8+ T cell (or apoptosis)

early steps in T cell maturation

thymus, pro-T cells (CD4-CD8-) undergo TCR gene recombination, pre-T cells with pre-TCR complex triggers TCR a gene recombination, CD4+CD8+ immature T cells express complete aB TCR

selection of mature T cells

positive selection (survive and express CD4+CD8+ and TCR) or negative selection (apoptosis)

positive selection of mature T cells

survive - weakly recognize self MHC with self peptides resulting in expression of either CD4+ or CD8+ (single-positive T cells)

negative selection of mature T cells

apoptosis - do not recognize self MHC with self-peptides (such as fail to express functional CD4+CD8+ or TCR) or strongly recognize self MHC with self-peptides

outcomes of maturation and selection of T cells

generate a collection of mature T cells that are able to recognize any foreign antigen peptides

recognized by antigen receptors

BCR (diverse microbes and toxins in their native form) and TCR (peptides presented by APCs)

BCR structure

H chains, L chains, V region (CDRs), C region