SELF - non SELF

Limfocite T si B

MHC - Procesare / Prezentare

Antigene
Cells of the specific immune
system

T cell B cell

Involved with cell mediated

immunity
Involved with humoral
Two types: immunity
helper T cells (CD4)
Secrete antibodies
cytotoxic T cells (CD8)

Generally eliminate Generally eliminate

intracellular pathogens extracellular pathogens
 B cells

Lymphocytes that react directly with

antigens
produced and mature in bone marrow
require stimulation from Helper T Cells
each B cell produces and wears a
unique antibody on its surface
clonal selection - when a B cell
encounters a matching antigen, it
begins to divide rapidly.
- some then become plasma cells that all
produce the same antibody (huge
numbers of antibodies -2000/second),
and then die. Others become memory
B cells.
the specific antibody produced by a
plasma cell is also secreted in soluble
form and circulates in the blood
 T cells
T cells display TCR as their antigen recognition protein
When stimulated they become Cytotoxic or Helper T cells
Secrete cytokines that recruit other cells of the Immune
System
Types of T cells:
helper T cells start the immune response
Inflammatory T cells (TH1) - Activate macrophages to kill
intracellular bacteria
Helper T cells (TH2) - Activate B cells to make antibody
cytotoxic T cells (CTLs)
Kill virally infected cells
Kill cells containing cytosolic bacteria
Kill tumor cells
suppressor T cells suppress the activities of other T cells,
helping to end the immune response
TCR Structure The TCR plus CD3 is referred
to as the TCR complex

The TCR is composed

of two protein chain:
or
Crz
Crz

The extracellular part

binds to MHC+peptide.
The intracellular part
signals through the
CD3 complex.

The TCR is always associated

with CD3 () and 2
(zeta) chain. These molecules
are involved in signaling the T
cell when it engages antigen
TCR Gene Rearrangement

Similar to Ig gene rearrangement:

Heavy () chain has V+D+J(+C) segments.
Light () chain has V+J(+C) segments.

TCRs can be either or .

The mechanisms are the same as in B cells.
Creates a highly diverse repertoire of TCRs.
 T cells

there are millions of different T cells the difference is

in their receptors (surface markers)

each T cell has a unique receptor that will recognize a

different foreign substance: V , VCDR1, CDR2,
CDR3

mature in the thymus, where they learn to tell the

difference between self and non-self
- critical, because if they did attack self,
autoimmune disease could result
 MHC & T cells
T cells have a requirement to recognise both the ANTIGEN and the
MHC molecule
This is because the molecular structure of the MHC-Antigen complex is
arranged so that some of the polymorphic amino acids of the MHC
molecule are in direct contact with the TCR
Therefore T cell recognition of antigen is said to be MHC
restricted.

Helper T cells (Th)

recognize peptide
associated with MHC
class II molecules

Cytotoxic T cells (Tc)

recognize peptide
associated with MHC
class I molecules
 TCR Structure accessory molecules

Accessory molecules
which also bind
MHC:

CD4 on helper
T cells, binds
MHC class-II.

CD8 on killer T
cells, binds MHC
class-I.
CD4 and CD8 Molecules

Transmembrane
molecules
Referred to as co-
receptor or
accessory
molecules
Member of the Ig
superfamily
T cells are either
CD4 CD4(+)
CD8(-)
CD8 CD4(-)
CD8(+)
HLA, MHC Clasa I si Clasa II

Clasa I Clasa II
Distribuie tisular Distribuie tisular
o Toate celulele o Celule prezentatoare
nucleate de Antigen (APC)
o Hematiile la unele Macrofage
specii Celule dendritice
Limfocite B
Celule stromale
timice
Functie Functie
o Prezinta antigene o Prezinta antigene
Ly Tc (CD8+) Ly Th (CD4+)
 Proteinele MHC Clasa I si Clasa II

Clasa I Clasa II

Lanul Alfa Lanul Alfa

o 3 domenii externe
o 1 transmembranar
o 1 rest C citoplasmatic
o Codificat in MHC
(crz 6p)
Beta-2 Microglobulina
o 1 domeniu extern
o nu e ancorat in
membrana
o fara rest citoplasmatic
o codificat in crz 15
o 2 domenii externe
o 1 transmembranar
o 1 rest C citoplasmatic
o Codificat in MHC
(crz 6p)
Lanul Beta
o 2 domenii externe
o 1 transmembranar
o 1 rest C citoplasmatic
o Codificat in MHC
(crz 6p)
Proteinele MHC I si MHC II
 MHC = CMH - Expresie

MHC I - pe toate MHC II - limitat, pe

celulele nucleate din imunocite: limfocitele B si
organism monocite (APC)
* Exceptii (He, celule ** Exceptii :
germinale) limfocitele T activate
Alctuit din 2 lanuri: Celule epiteliale / timus
ancorat - alfa cu 3 Alctuit din 2 lanuri:
regiuni ancorat - alfa cu 2
liber - beta 2 (2-mg) regiuni
Leag strns oligopeptide ancorat - beta cu 2
mici (aproximativ 9 Aa) regiuni
Sunt extrem de polimorfe Accept oligopeptide cu cel
puin 15 Aa
Polimorfism limitat
 Distributia tisulara a exprimarii MHC

Expresia moleculelor MHC

difera de la tesut la tesut.
Moleculele MHC clasa I sunt
exprimate pe toate celulele
nucleate, foarte bine
exprimate pe celulele
hematopoietice.
Moleculele MHC clasa II
sunt exprimate nativ doar
pe un subset de celule
hematopoietice si de
celulele timice stromale,
alte celule exprimndu-le
doar in urma expunerii la
citokine inflamatorii
(interferon-).
 MHC & Antigenele
MHC Clasa I MHC Clasa II-a
prezinta peptide
endogene
originea peptidelor: self
sau de origine virala
deoarece MHC Clasa I
este prezent pe toate
celulele din organism,
orice celula poate
interactiona cu limfocite
T, daca este infectata
cu virus
prezinta antigene
exogene care au fost
fagocitate si procesate
(de ex. bacterii) sau
Ag care nu necesit
procesare
procesul este realizat
de celule
profesionale (de ex.
Macrofage, Celule
dendritice, LyB)
 Structura moleculara a MHC clasa I

Doua structuri in helix

ale zonelor 1 si 2 ale
lantului formeaza
peptide-binding groove al
moleculei

TCRs se leaga la vrful

moleculei, care contine
cele mai polimorfe reziduuri.
MHC clasa I

2-microglobulina
Structura molecular a MHC clasa a II-a

Cele doua domenii

polimorfe (1, 1)
formeaz peptide-
binding groove al
moleculei

TCRs se leaga la
vrful moleculei,
care conine cele mai
polimorfe reziduuri.
MHC clasa a II-a

DR chain
Polimorfismul MHC clasa I

Variatia allelica survine

la nivelul unor situsuri
specifice ale moleculei
MHC. Aceste situsuri
corespund aminoacizilor
care vin in contact cu
antigenul.

Variabilitate similara
se observa in cazul
moleculelor MHC clasa
II.
 Polimorfismul MHC clasa I

Structura cristalina
(clarificata trziu - 80) a
dovedit existenta unui sant
alcatuit din foi -pliate anti-
paralele (la baza santului) si
-helixuri (pe laturile
santului).
Regiunile 1 si 2 ale MHC
clasa I si 1 / 1 ale MHC
clasa II formeaza imaginile
in oglinda cu rolul de a
alcatui santul de legare al
peptidului antigenic.
Aminoacizii pozitionati de-a
lungul santului interactioneaza
(prin legaturi de hidrogen si
atractii de tip ionic) cu amino
acizii peptidului, stabilizindu-l
Expression of HLA is co-dominant

Father Mother

Kids
 Polymorphism and polygeny of MHC

Two different properties make it difficult

for pathogens to evade immune responses

Definitions:

Alleles: different forms of one

gene
Allotypes: different forms of one
protein (isoforms)

Polymorphic: alternative forms of

one gene = Many alleles
Oligomorphic: a few forms of one
gene = Few alleles
Monomorphic: no polymorphism

Homozygous: same allele on both

inherited chromosomes
Heterozygous: different allele on
both inherited chromosomes
 The MHC gene region

http://www.ncbi.nlm.nih.gov/mhc/MHC.fcgi?cmd=init&user_id=0&probe_id=0&source_id=0&locus_id=0&locus_group=0&proto_id=0&banner=1&kit_id=0&graphview=0
Genele MHC

Determina capacitatea unui organism de a

interactiona cu antigene
Sansa unei persoane de aceeasi etnie sa aiba gene
MHC compatibile este de aprox 1:1000
Genele MHC sunt denumite HLA de la human
leukocyte antigen
La alte specii au denumiri diferite (la soarece
genele sunt denumite H-2)
Genele MHC I si MHC II sunt niruite pe acelai
cromozom 6p
Genele MHC sunt poligenice i polimorfe
Genele MHC

Genele MHC utilizeaza loci diferiti pe cromozomul 6p

Genele MHC sunt mostenite de la ambii parinti, combinatia
genelor numindu-se haplotip

Expresia genelor MHC este co-dominanta

Indivizii pot exprima 2x3 subclase de gene I si 2x3(4)
subclase de gene II

Alte gene ale sistemului imun nnscut sunt localizate ntre

cele dou regiuni (I i II) n acelai ciorchine (cluster)
- C2, C4, factorul properdinic B, TNF
Major Histocompatibility Complex
Human MHC (HLA) encoded on cromosome 6
Genele MHC

Gradul de polimorfism variaza in cele doua clase

(Polimorfism = numarul de allotipuri sau izoforme posibile)

Genele MHC Clasa I sunt denumite: HLA-A (414 allele), HLA-B

(728), HLA-C (210), HLA-E (6), HLA-F (1), HLA-G (15)

Genele MHC Clasa II-a sunt denumite: HLA-DP(23 allele),

HLA-DP(120 allele), HLA-DQ(32 allele), HLA-DQ(68
allele), HLA-DR(3 allele), HLA-DR(503 allele), HLA-DM
(10), HLA-DX, HLA-DO (16), HLA-DZ

In consecin, moleculele MHC sunt limitate n capacitatea lor

de a lega peptide
Aceasta se numete restricie MHC
Figure 5-13
 Human Leukocyte antigen (HLA=MHC
in humans) polymorphism - alleles

http://www.anthonynolan.com/HIG/index.html
Figure 3-24 part 1 of 2

Heavy Chain

Heavy Chains
Diversitatea imunologic generat de
locusurile MHC
 HLA Diversity - 2 x 3 HLAs per person

http://www.stanford.edu/dept/HPS/transplant/html/tt_1.html
Celulele prezentatoare
de Ag - APC

Macrofage/monocite
Celule Dendritice
(Langerhans cells)
Ly B
Proprietatile
APC
 RELATIONSHIP BETWEEN PATHOGEN AND MHC
COMPARTMENTS: A TWO-PRONGED APPROACH
TO ANTIGEN PRESENTATION

Two places for pathogens to be found within eukaryotic cells, cytosol/endogenous

and vesicles/exogenous.
Two pathways for antigen presentation for peptides (MHC class I and II).
One place for antigens to end up in order for the TCR to recognize foreign antigen-
on the surface of the cell in the context of MHC.
Demarcation
between MHC
class I and
class II
Processing
Pathways
 MHC Class I pathway

Figure by Eric A.J. Reits

 Endogenous Antigen Processing - Generation of
Peptide-class I MHC Complexes

Calnexin
Tapasin +
Calreticulin

TAP =
Transporter
associated
with Ag
Processing
 MHC class II pathway

Figure by Eric A.J. Reits

 Exogenous Antigen Processing
APC engulf antigens (bacteria, etc.)
MQ, dendritic cells eat anything
B cells only endocytose Ags bound by their mIg
receptors
Ag peptides generated in endocytic vesicles
Demarcation between MHC class I and
class II Processing Pathways
MHC Proteins

Ambele tipuri de proteine MHC sunt

importante pentru activarea Ly T:
Class I proteine MHC
o Sunt recunoscute de Ly T CD8
o Prezenta peptide (antigene) endogene

Class II proteine MHC

o Sunt recunoscute de Ly T CD4
o Prezenta peptide (antigene) exogene
Co-receptors on Helper and Killer T cells
Prezentare Ag
Toxins that act as superantigens:

superantigen binds to
regions outside the
normal binding sites on
TCR, MCH II

result is massive T
cell activation, cytokine
release, systemic
inflammation

Enterotoxin A - Staphylococcus aureus