3 signal th1, th2, CCR7, MHC1 and MHC2, Mhc1 and 2 presentation, cross presentation, Why

mHc1 or T cell stimulation is important, HLA-DM

Immuno (lecture 3)
Bir t hücresi ve b hücresi Farklı antijenleri tanıyor. B hücresinin nükleik asitleri, karbonhidratları,
lipitleri tanıyabildiğini, t hücrelerinin sadece peptid structure’ı tanıyabildiğini ve bu peptidin,
Professional antigen presenting cell tarafından sunulduktan sonra t hücresi uyarılır. (3 sinyal
gerekli)
B hücresinin uyarılmak ve antibody sentezlemek için bir hücreye ihtiyacı yok. B hücrelerininde
salgıladıkları antikorların subsetleri var ( IGm, IGg,IGi, IGa) işte bu farklılaşmalarda ve antikorun
afinitesinin artmasında, helper t hücresi ile interactionı çok önemlidir. ( ama uyarılması İçin
önemli değildir)
Professional antigen presenting cell and atypical( enfeksiyon veya inflammation esnasında
MHC2 molekülünün ekspresyonu artması ile oluşan)

First step of adaptive immunity (antigen capture and presentation to lymphocytes)

⁃ dendritic cell, antigen presenting cell, surface molecules on the antigen presenting cell)
⁃ What is the function of the this kind of surface molecule (MHC1 and MHC2)

✓ How they present the antigen to naive CD8 T cells and naive CD4 T cells?
#Adaptive immunity divided into two humoral and cell mediated immunity.
#B cells responsible for the humoral immune response and they produce the antibodies.( B cells
recognize protein antigen by their surface receptor (BCR).)
#T cells ( helper T cell (CD4+) , cytotoxic T cell ( CD8) )
#For humoral immunity, B cells have a receptor on the surface (BCR). This receptor can be
recognize the carbohydrates, lipid, nucleic acid and protein.
#T cells just recognize the peptide fragments.(10-30 amino acid depend on the which MHC1 or
MHC2 present it), and this peptides should be present with the professional antigen presenting
cells such as dendritic or macrophage cells.

✓ Why mHc1 or T cell stimulation is important?

Inject the antigen, dendritic cell take the antigen. They insert the lymphatic system and migrate
the lymphoid tissues. In the lymphoid tissues, there are naive CD4 and CD8 T cells. For
stimulation of the correct T cells, dendritic cells ingest the pathogen and break into the their
peptides. Dendritic cells presented the this peptide with MHC for T cell activation (signal 1)
**Protein beaks into the peptide and this peptide presented with the MHC molecule to naive T
cell. ( signal 1)
**The signal 2 is costimulator molecule such as Cd80/86 and CD40 which is expressed by the
antigen presenting cells binds the cd28 which is the costimulator receptor and it is on the T cells.
**The signal 3, dendritic cells secrete the different cytokines depend on the infection, if this
cytokine such as IL12 that time this naive CD4 helper T cell differentiate into TH1 (viral infection)
T cell , If this cytokine is IL4 that time this naive CD4 T cells differentiate into the TH2 (allergic
reaction) helper T cell.
( cytokines determine the which kind of T cells will be differentiate from naive CD4 helper T cells)
****ÖZET
For T cell activation, 3 signal is needed. The first signal is MHC1 and TCR interaction. Second
signal is CD80/86 and CD28 interaction. Third signal is cytokines.

#B cells don’t need the dendritic cells for activation. When they recognize the protein, nucleic
acid, lipid, polysaccharide, they can activated and secrete the antibodies.
But they needs the T cell help, after B cells and T cells interaction, B cells produce high affinity
antibodies which is important for the neutralization. ( B cells should be present one peptide to T
cells. )

✓ B cells don’t need a antigen presenting cells but T cells need a antigen presenting cells for
activation. This antigen presenting cell’s divided into two. Professional and atypical.
⁃ 3 professional antigen presenting cells ( B cells , dendritic cells and macrophage) ( they have
capacity to induce T cell activation)
⁃ 3 atypical antigen presenting cell ( mast cell, basophils, eosinophils), they are not actually
antigen presenting cells but during the infection condition, they can express the MHC2 molecule.
( they don’t have a induce the naive T cell stimulation)

# Dendritic cell main T cell stimulator cell or professional antigen presenting cells.
When virus insert the our lungs, dendritic cells takes up the antigen because they have a toll-like
receptor, nod-like receptor, rig-like receptor, they can recognize the pathogen with pathogen
recognition receptor. They start to express CCR7 ( this receptor important for dendritic cell
migration, increase movement). In the lymphoid tissue there are CCL19 and CCL21 ( these are
the ligand for the CCR7). Therefore, dendritic cells migrate correct lymphoid tissues. Dendritic
cell contact with the naive CD8 or CD4 T cell.

## after the toll-like receptor activation, cells movement, secretion and surface to the molecules
expression is increase (increase their movement ( migrate the one infection to lymphoid tissues),
they can secrete cytokines, they express more surface receptor for the immune cell activation. )

have to induce adaptive immunity. Dendritic cells migrate secondary lymphoid tissue (lymph
nodes) because naive CD8 T cell there.

✓ ####ÖZET
## after the infection, dendritic cells recognize the pathogen and ingested them. Dendritic cells
Insert the lymphatic vessels and migrate the lymphoid tissues for presenting the antigen to
correct naive T cell.( dendritic cell-naive T cell interaction) and for this migration they express
high CCR7 which in peripheral area (mature dendritic cell has a CCR7) and this CCR7 is ligand
for CCL19 and CCL21 which in the lymphoid tissue, dendritic cells presented the pathogenic
peptide with MHC1 or MHC2( depending on the peptide conditions or antigen) . If T cells
recognize the this peptide, it activates and starts to proliferation.
MHC1 and MHC2

##MHC1 is the surface molecule, all the cells which has nucleus, express MHC1. MHC1 is
heterodimer structure so it is consist of the 2 different polypeptide. The fist alpha peptide consist
of alpha 1,2 and 3 lobs. And the peptide for presentation, it is located on the between alpha 1
and 2. 1 transmembrane structure. For peptide sites, it should be 8 to 10 amino acid. *So that,
their antigen binding capacity also different.

##MHC2 molecule mainly express on professional antigen presenting cells. It is also

heterodimer structure and it consist of alpha and beta. The peptide binding structure is between
alpha 1 and beta 1. 2 transmembrane structure or 2 polypeptide insert. For peptide sites, it
should be 10 to 30 amino acid. When peptide presented with MHC 2 that time helper T cell
activated.

✓ Why one antigen or peptide presenting with MHC1 or MHC2? What is differences?
The difference is antigenic condition. If one antigen is ingested or phagocyte and this antigen is
extracellular antigen, that time it will be presented with MHC2 molecule.
If the peptide inside the cell ( proteins in cytosol), that time it will be presented with MHC1.

*** MHC moleküllerinde Farklı peptidler sunulabilir, 3D structure ları uygunsa, ama her seferinde
sadece 1 tane peptid sunulabilir.
with MHC molecule, carbohydrate, lipid, nucleic acid can’t presented. ONLY PEPTIDE SHOULD
BE PRESENTED.

*****if antigen presented with MHC1, that time CD8 T cells will be activated. If this peptide
presented with the MHC2, that time helper T cells ( CD4 )will be activated.

✓ MHC2 presentation (exogenic antigen presentation) ** it should be presented by dendritic

cells, B cells or macrophage to naive CD4 T cell)
Antigen should be out of the cell( extracellular area), it can be taken by phagocytosis by dendritic
cell. Endosome which contain protein antigen combine with the lysosome. Because lysosome
contain digestion enzyme, protein antigen breaks into the peptide in the cytoplasm. At the same
time, MHC2 protein expressing in endoplasmic reticulum as MHC2 alpha and beta polypeptide.
In ER, there are a lot of peptides and some of the this peptides can binds to cleft. Therefore,
immune system cells use the invariant chain (protein arm digested by the lysosomic enzyme,
only remain CLIP bud) CLIP bud)), block or close to MHC2 cleft which is peptide binding site. In
ER, help of the invariant chain, peptides couldn’t bind the MHC2 molecule. MHC2 and invariant
chain complex move to the golgi and than in cytoplasm with exocytic vesicles ( contain MHC2
molecule and CLIP ) combine with the late endosome which contain HLA-DM. CLIP move from
MHC2 to HLA-DM because its affinity is higher and correct peptide presenting with MHC2
molecule on the surface of the professional antigen presenting cells. The peptide is presented by
the MHC2 molecule and it interact with the naive CD4 helper T cell TCR.
** MHC2 and peptides combine in the cytoplasm.
✓ MHC1 mechanism
Virus infected the dendritic or epithelial cells because all the cells with nucleus can express
MHC1 presentation but they don’t have a CD8 t cell stimulation capacity because don’t have a
costimulator molecule which express CD80/86 ( signal 2).

If antigen is intracellular, virus enter the cell and produce their protein. This protein recognized
by the ubiquitinated protein. This ubiquitinated and viral protein goes to proteasome. In
proteasome, they spliced into the peptides. This peptides goes to ER which contain TAP1 and
TAP2 molecules and these molecules help peptides to come into to ER. ***Peptide and MHC1
molecule combine in the ER. They goes to golgi and they secrete the as a exocytic vesicle.
Than, peptide(antigen) presented with MHC1 molecule on the cell surface of the dendritic cell to
CD8 cytotoxic T cells. FOR THIS REASON, INFECTED CELL DONT WANT TO EXPRESS
MHC1 MOLECULE BECAUSE ACTIVATED CD8 T CELL CAN BE RECOGNIZE AND KILL THE
INFECTED OR CANCER CELL.

✓ MHC1 and MHC2

⁃ In MHC2 presentation, the peptides between the alpha 1 and beta 1. In MHC1 , the peptides
between alpha 1 and alpha 2.
⁃ In MHC2 presentation, dendritic cell, mononuclear phagocytes, B lymphocytes, endothelial
cells, thymic epithelium. MHC1, all the nucleated cells.
⁃ For MHC2 presentation, induce the CD4 T cell activation. For MHC1, induce CD8 T cell.
⁃ For MHC2, source of protein antigen should be endosomal extracellular antigen. For MHC1, it
should be cytosolic protein(synthesized in the cell)( antigen is in the cytoplasm)
⁃ For MHC2, endosomal protease breaks protein into peptide. For MHC1,protein into the
peptides breaks by cytosolic proteasomic enzyme
⁃ MHC and peptide combining location is different, MHC2 in the cytoplasm in the endosome and
MHC1 in ER
⁃ Antigen loading proteins is different, for MHC2 are invariant chain and HLA-DM, for MHC1 is
TAP
**one MHC1 or MHC2 molecule can be present or carry (bind) the different peptides. But each
time, it should be one peptide. At the same time, one MHC molecule shouldn’t present 2
peptides. But they can be different peptide but they have a similar amino acid and 3D structure.
***( MHC molecules present different peptides. If their 3D structure similar. Each time only one
peptide presenting.)
✓ Cross-Presentation (antijenlerin çapraz sunumu)
One exogenic antigen presented with MHC1 molecule.( Theoretically, Exogenic antigens should
be presented with MHC2 and induce CD4 (helper t cell), intracellular antigens should be
presented with MHC1 and induce CD8 ) but that time one specific dendritic cells population have
a capacity to presented exogenic antigen with MHC1 molecule ( cross presentation)
Cancer cells are extra

MHC genes, mother and father express codominantly.

Mhc1 and MHC2 processes
Antigen presentation
Which cell population is important for the T cell stimulation ?

✓ Antigen presenting cells and They are main function is the present the antigen to naive T cell,
these antigen should be presented as a peptide. The main antigen presenting cells are dendritic
cells, B cells and also macrophage. They can be either present the antigen or peptide with the
MHC1 or MHC2. If antigen presenting cell present the antigen or peptide with mhc1, CD8+ T cell
activated. If peptide presented with MHC2, CD4 helper T cell activated.
✓ T cell needs to 3 signal for stimulation. First one is the MHC-TCR interaction. T cells express
the TCR receptor and this receptor recognize the peptide on the mhc1 or mhc2 molecule
depend on the T cell. Also, the second signal is the costimulator molecule, dendritic cells or
antigen presenting cells express CD80 or CD86 and CD40, this kind of molecules binds the their
receptor on the T cells. Third signal is the cytokine, subset differentiation for the helper T cells.