Class 4 lymphocyte development

what is considered as an antigen

foreing antigen

• infectious

  • pathogens, as viruses, bacteria protozoa

• non-infectious

  • enviornmental, like hayfever, milk allergy

self antigen

• tolerance

B0cell receptor (BCR)

interact with large are of intact antigen

• on the surface of the pathogen

• no processing of the antigen is needed

  • recogntion in exracellular fluids

T cellr eceptor (TCR)

recognizes processed antigne

• small peptides

• presented by antigen presenting cells (APC)

  • included, presented with major histocompatability complex MHC)

specificity of the receptors

randomly selected gene segmetns, that are the N terminal (recognitoin part)

BCR a tetramer with 2 heavy chains and 2 light chains

TCR a heterodimer with alpha and beta subunit

both have a variable region where antigen is recognized

4 elements that cna be used for speicifc recognition

bcr light chain, bcr heavy chain

tcr alpha chain, tcr beta chain

B cell receptory diversity

diversity by selecting from a series of genes encoding for different regions

heavy chain variabile region is encoded by

• variable (V)

• diversity (D)

• joining (J)

cleavage and ligation DNA (VDJ recombinase) by enzyme RAG1&2 (recombination activating genes)

light chain

no diversity segment compared to heavy chain

BCR can be more diverse

alternative junctional recombinaiton

somatic mutatino single nucleotide substitutions (point mutations)

gene conversion(V pseudogenes)

domestic animals limited number V, D and J (Heavy andlight)

all in immature B cells

B cell development

B cell develop in bone marrow

BCR

B cell maturation in boene marrow

Final stages of maturation

• bursa of Fabricius (chickens)

• spleen (humans)

• ileal peyers patch (ruminants)

BCR that binds to self antigens in the bone marrow, apoptosis

REceptor editing

BCR specific, then B cell beocme part of the recicrculating poo

apoptosis

programmed cell deathT

T cell development

TCR recognize processed antigen

T cell develop in the thumus

CD4+ AND CD8+ cell

TCR alpha and beta chain

TCR always needs to connect to MHC

CD4 to MHC II

CD8 to MHC I

CD4 helper T cells 0 cytokine

CD8 killer T cells

CD3 for the intracellular signaling

TCR

Alpha chain, beta chain

variable, constant, joinging

duplication in the genome, human, mice, dogs, horses

pig, sheep, cattle three replicates

more sets of D-J-C

selection in the thymus

receptor need to be functional with the adaptive immune system

need to interact with MHC

self antigens, no reaction

T cell maturation

TCR expression ,both CD4 and CD8 expression

positive selection

• into the thymic cortex, epithelial cell MHC I and MHC II

• single expressoin

negative selection

• thymus DC with self antigens ( in the thymus loot of self antigens)

Connection innate and adaptive system

How and why do APC and T cell interact

Ag is being processed and via MHCI or MHCII presented to T cells

To activate the adaptive immune system

Antigens are bound on MHC molecules, this is detected by TCR

Major histocompatibility complex

cell mediated immunity

part of the adaptive immune system

antigen presentation to T cells

B cell recognize non processed antigens, complete pathogens (BCR do not need MHC)

T cell response mediated by APC and MHC

T cell

does not recognize free antigen (under normal conditoins)

T cell receptor (TCR) binds

antigen (peptides) incombination with a self marker (MHC molecules) on the surface of an antigen presenting cell APC): such as dendritic cells, B cells, macrophages via class II MHC, or virus infected or tumour cells (class I MHC)

Two major tpes of self markers present on vertebrate cell membranes

MHC class I membrane molecles, on all nucleated cells

CD8+ Tcut. that react to MHC class I + (intracellular self or viral) antigen

MHC class II membrane molecules, on APC

CD4+ TH that react to MHC class II + (extracellular) antigen

MHC

MHC I (on all nucleated cells)

alpha chain 3 extracellular domains

B2 microglobulin

MHCII (on APC)

2 TRANSMEMBRANE DOMAINS, 2 ALPHA CHAINS, 2 BETA CHAINS

Antigen presenting cells

MHC expression

• dendritic cells

• macrophages

  • B-cells

Histocompatibility antigens

Class I A3 AND B2, CLASS ii A2 AND B2 are relatively conserved and homologous to Fc domains of IG

Class I A1 AND A2, CLASS ii A1 AND B1 are variable

Variability

Variability within the alpha 1 and alpha 2 of MHC - I and alpha 1 and beta 1 of MHC ii

Those are the peptide binding groove

• folded such B sheets at the bottom and aloha helix at the sides

• this forms the peptide binding specificity

basis structural rearrangements similar as for BCR

peptide binding to MHC

Processed antigen

For MHC-I peptide are 8-10 aa

For mHCII peptide are 13-25 aa

MHC class I processing

presenting of endogenous antigen, those that are in the cytoplasma, no phagocytose

MHC class I

endogenous antigens

self antigen

tumour antigen

allo antigen

viral antigen during viral replication

Intracellular bacteria, like TBC, Coxiella

processing of endogenous antigens

proteins targeted uqiquitine

towards proteasome

enzyme degradation

translocation by TAP1 nad TAP2 to the ER

in the ER new syntehsized MHC I, peptide binds (or not)

MHC-I via golgi cell surface

Detetion by CD8+ cells via TCR screening peptide

MHC-II

Most antigens are extracellular, actively taken up by endosomal vesicles (APC), processed and presented to MHC-ii

APC

DC, macrophage, B-cell

synthesises MHC in ER, nota also MHC-I in the ER

Need to keep endognoues and exogenous pathways separated

Use of invarirant chain, to keep MHC-II locked, also transprot to the MIIC compartment via golgi

Exogenous antigen

bacteria, viruses, fungi, helminth, environmental, pollens, dust mite, food stuff

uptake into APC

enhancing of uptake, recpetor (PAMP), opsonization via AB, complement system (C3b)

processing of antigen

phaogsome or endosome, processed into smallr antigens from complex structure

enzymes in lysozome process ag into 10-30 aa peptide. into groove of MHC-II recognition APC and CD4+ cell

Dendritic cell (DC)

important APC

Activate T cells in tissue

primary adaptive immune response

COnventional DC

• Migratory in body tissue, sampling ag, migrate to lymphoid

• lmphoid, remain lymp nodes

non conventional DC

• plamacytoid in lympoid and no lympoid (Liver), pprr, INF

• Monocyte derived, inflamed tissue

• langerhans

mucosal tissue (lung adn gut)

capture Ag to the regional lymphoid,

optimal dendritic morphology to contact with T cells CD4+

macrophage and B cell

phaogyctoses and APC (MHC-II)

Ag fromt he bloodstream

activated macrophages can become multinucleated giant cell

B cell Ag processing via MHC-II

Ag boudn via BCR, internalization endosome

Inheritance of MHC

region in genome cluster of immune response gens

original found on leukocytes (leukocyte antigen esystem)

hla human leukocyte antigne

class II region (d region)

number of genes within complex duplication isn evolution

multiple genes encoding MHC - polygeney

MHC genes are co-dominant

each indivudual expresses one of the possible polymorphic variants from each locus on their cells

There are two sets of MHC genes (maternal and paternal)

each person expresses 6 clas I molecules, one from each maternal andpaternal A<B<C locus

THE MHC

A linked series (complex) of genes located on one specific chromosome

encode the histocompatibility molecules

MHC genes are highly polymorphic with many possibile allelic variants or allotypes

MHC genes duplicated within the complex

Gene ducplication and polymorphism provided and evolutionary advantage as the mammalian MHC is ore complex than simple life forms

MHC fingerprint

unique, the duplication of genes and polymorphism

Polygenic and polymorphic

note breeding, inbred, number of differnt genes will reduce

results susceptible, disease

however, polygenic and polymorphic, different alleles with own ag binding repertoir, co dominalty expressed, most outbred heterozygous

haplotype

maternal and paternal

MHCI AND MHCII close together on the genome, both togheter inherited as set

MHC role

MHC involved in positive and negative selection TCR

Variation MHC determine

resistance for infection

response to vacicination

susceptibility for immune diseases

loot of disease are immun related aslo to due to MHC inheritance

Covid/other dieseases

identification for regirstion purposes - pedigree dogs

maybe associated (negatively) to production traits

olfactory, odor for mating, selecting for heterozygositi

MHC role in transplantation

autograft

isograft (twins)

allograft, close related MHC type

rejection, donor leukocytes, go to lumpj nodes, activate T/B cells

Xenograft, from other species, gene ediitng possibiliteis