Antigen & Lymphocyte Development

T cells

Circulates as naive T cells, secretes cytokines/kill, require antigenic properties to be presented to them in MHC on cell surface

MHC molecules

MHC 1 & MHC 2, most polymorphic loci in body, in humans = human leukocytes antigens (HLA)

Every human has 6 class 1 genes

3 mom, 3 dad

HLA-A, HLA-B, HLA-C (#)

Everyone has 6 class 2 genes

3 mom, 3 dad

HLA-DP, HLA-DQ, HLA-DR (#)

MHC functions

Present peptides on host cell surface to a T cell w/TCR, presentation is required for function of T cell arm for adaptive immune response, TCR only recognize epitopes when complexed w/ MHC

MHC 1

• all nucleated cells

• Presents CD8 T cells

• Single alpha chain w/ 3 domains

MHC 1 structure

• cleft binds 1 peptide @ a time

  • Different peptides can bind

• Binding pockets are closed

• Peptides are anchored to pocket @ ends (anchor residue)

MHC 1 peptides

• produced inside cell

• Endogenous antigens through endogenous pathway

• Antigens are loaded onto MHC 1 in ER

• Peptide loaded

• Allows CD8 T cells to see what’s going on inside

MHC 2

Expressed on APCs (DC, B cells, macrophages), presents to CD4, 2 polypeptide chain w/ 2 domains (alpha & beta), binding cleft = a1 + b1, 1 peptide at a time

MHC 2 structure

Ends of binding groove are open (allows for longer peptide) and anchor residue are spaced along the peptide length

MHC 2 peptides

• Loading occurs in phagolysosomes

• Derived from exogenous antigens through exogenous pathway

• Allows CD4 to see what’s going on inside

Processing & Presentation of MHC 1

Occurs in cytoplasm by proteasome, MHC 1 synthesized & assembled in ER

Processing & Presentation of MHC 2

Processing of endogenous occurs in phagolysosome, MHC 2 synthesized & assembled in ER

Antigens

Several type that can elicit an IR

• proteins

• Polysaccharides

• Nucleic acids

• Lipids

• Superantigens

Proteins

Best type of AG, have to be big, more complex = vigorous response, more visible to AB = more likely to elicit IR, more epitopes on single protein = better AG

Polysaccharides

Elicit IR due to repetitive structure, elicit response if bounded/associated w/proteins, T indep. AG, not processed/presented

Nucleic Acids

Poor activators, increased when bound to protein, SLE = response by ABs made to Nucleic acids bound to histone proteins

Lipids

Not generally immunogenicity unless w/ protein/polysaccharide, glycolipids & lipoproteins = most potent stimulators

Superantigens

AGs that can activate T cells regardless of T cell’s AG specificity, produced from pathogenic viruses & bacteria, leads to uncontrollable activation of T cells, bind to MHC 2 outside of grove & outside TCR, can simultaneously activate a TON of T cells

Antigen

Any material/molecule that can bound by an AB and/or T cell (after MHC presentation)

Immunogen

Antigen that can elicit an immune response

Adjuvant

Allows for longer/enhanced exposure of an immunogen to the immune system, make AG bigger = easily phagocytosed, mixed w/ AG but DO NOT form stable linkages

Hepatens

Can physically bound by ABs (AGs), but CANNOT induce IR by themselves, NOT IMMUNOGENIC, hepatens + carrier protein = induce IR

Hepaten + carrier

Physically, covalently bounded, NOT immunogenic

Antigen + Adjuvant

DO NOT form stable linkages/ not physically bounded, immunogenic, adjuvant prolong/ enhance/ accelerate IR

Immunogen size

• small molecules DO NOT elicit much immune response

• Max stimulation w/ large molecules (>10,000 Da), 100,000 polysaccharides, less soluble, more visible to ABs & easier APCs to phagocytes

Immunogen chemical attributes

• Complex molecules (lots of side chains) = good Immunogen

• Heteropolymers > homopolymers

• Charged > neutral

• Hydrophilic > hydrophobic

Degradable Immunogen

Must be able to be presented to T cells (phagocytosed & broken into small piecies)

Immunogen density

More epitopes> more ABs to bind> more complement activated/opsonization

Immunogen foreign-ness

More unlike our molecules> better immunogenicity (easier to recognize non-self)

Factors that affect Immunogenicity

• genetics

• Age

• Dosage

• Route of administration

Immunogenicity genetics

Genetic defects = no/ decreased response

Immunogenicity Age

Infants born w/ still developing immune system, immunity wanes w/ age

Immunogenicity dosage

Too high = anergy (T cell tolerance)

Too low = failure to elicit response

Immunogenicity route of administration

Determines which cell & organs will be activated & isotype of AB produced

Oral = IgA

IV = IgB

Epitopes

• small parts of large antigen recognized by BCR/TCR

• AGs large variety & large # of epitopes

• B & T cells DO NOT (usually) have same epitope

BCR/AB Epitopes

• must be accessible

• Sequential/ discontinuous

TCR Epitopes

• must be sequential

• Does not need to be on surface/ external face (nuclear/cytoplasmic protein & inside folded protein)

• Recognized by TCR w/ proper presentation (hydrophobic epitopes presented to T cells via CD1)

T cells mature in…

Thymus = secondary lymphoid organs

B cells matures in…

Bone marrow = blood & populate secondary lymphoid

B cells

• mediators of adaptive immune system

• Provides ABs

• BCR recognizes AGs & activate B cell

• Has sequence that anchors into B cell membrane unlike ABs

• All ABs & BCR made by 1 cell/ plasma cell that differentiate from that B cell bind the same antigen

B cell Maturation

• begins in bone marrow

• Must commit to lymphoid lineage

• B cell progenitor enters pro-B cell stage to begin B cell- specific steps of development

B cell Gene Rearrangement

• genes undergo rearrangement to produce variable regions of AB (VL & VH)

• Provides diversity

• Process fails = apoptosis

Heavy chain of gene rearrangement

• 4 genes

• V = variable

• D = diversity

• J = joining

• C = constant

Light chain of gene rearrangement

• 3 genes

• V = variable

• J = joining

• C = constant

Lymphocytes

Pro B cells, pre B cells, immature B cell, mature B cell

Pro B cells

Heavy chain rearranges

Pre B cells

Light chain rearranges

Immature B cell

H & L chains = full IgM on surface

Mature B cells

IgD made & expressed on surface, technically still a naive B cell because it has not encountered AG yet

Mature, naive B cell

IgM & IgD BCR on surface

Additional changes to BCR occur in…

Secondary lymphoid tissues & after AG interaction

Ig heavy chain rearranges…

First

2nd checkpoint

BCR in immature B cell promotes survival to preserve cells that express complete AG receptors

Cell DOES NOT bind to AG in 2-8 weeks

Apoptosis

T cells

• mediators of adaptive immune system

• Combat microbes ingested by phagocytes & live in cells/ microbes that infect host cells

• DOES NOT bind native AG (must be processed & presented)

• Mediate defenses against extracellular microbes, help B lymphocytes to produce ABs & destroy cancer cells

CD4

Th

CD8

Cytotoxic T cells (CTLS)

AB & TCR structure

Will express either aB (CD4 & CD8) = 80% or I theta = 10%

TCRs = heterodimers of transmembrane polypeptide chains

ABs w/ high affinity

Neutralize different microbes & toxins

TCR only recognize

Peptide MHC complex

Life of Lymphocyte

IL-7 > thymus > signal maturation

Thymus selection

• TCR genes rearrange = make sure thymocytes can be activated & do not recognize self

Positive selection

• Weak recognition

• Self MHC recognition (fails=apoptosis)

• Linear choice CD4/CD8

• Function of T cell set

• Double (+) thymocytes become single (+) thymocytes that recognize own MHC

Negative selection

• strong recognition

• Against self-antigen (don’t want self-reactive T cells)

• Remove thymocytes that recognize self-antigen so they don’t replicate

• DC in thymus present self AGs to thymocytes

• Thymocytes recognize self-antigen presented by DC = apoptosis

Development of lymphocyte selection occurs while…

Innate immunity “buys time”

Immature lymphocytes strongly recognize self-antigens

Negatively selected & prevented from maturation

T lymphocytes that recognize peptide antigens displayed by self MHC & ensure recognition of appropriate MHC matches receptor

Positively selected