Antigen-presenting cells

The cells that can process and present antigens (MHC-peptide) to T cells

Professional APC
Dendritic cell
Macrophage
B lymphocyte

Nonprofessional APC
Several other cell types, classified as nonprofessional antigen-
presenting cells, can be induced to express class II MHC molecules or
a co-stimulatory signal.
Many of these cells function in antigen presentation only for short
periods of time during a sustained inflammatory response.

Antigen Processing & Presentation
Antigen processing and presentation occurs within a cell that
results in :
i. Fragmentation ( proteolysis) of proteins
ii. Association on of the fragments ( proteins / peptides) with
MHC molecules
iii. Expression of peptide- MHC molecules at the cell surface
where they can be recognized by T cell receptor on the T
cell receptor
However,
The path leading to the association of protein fragments
differs for Class 1 and Class II MHC molecules .
The MHCI molecules are involved with the degradation
products derived from intracellular ( endogenous ) proteins
in the cytosol.
MHC Class II molecules presents fragments derived from
extra-cellular (exogenous) proteins that are located in an
intracellular compartment.


Processing and presentation pathway
MHC class I pathway----endogenous antigens Cytosolic pathway
MHC class II pathway---exogenous antigens Endocytic Pathway

Ag is processed thru 2 separate pathways:
*MHC I interacts w/ peptides from cytosolic degradation
*MHC II interacts w/ peptides from endocytic degradation
Processing Endogenous Ag:
the Cytosolic pathway
Cellular proteins are constantly regulated; most have
a brief half-life and are turned over the same
holds true for endogenous Ags!
Processing of endogenous Ag involves 3 activities:
Peptide generation from proteolysis
Transport to ER
Peptide binding to MHC I
Endogenous Ag processingpeptide
generation
Proteins targeted for lysis
combine w/ a small protein
ubiquitin

Ubiquitin-protein complex is
degraded by a proteosome

Specific proteosomes
generate peptides which can
bind to MHC I
Endogenous Ag processing
transport to ER
Peptides from proteolysis
bind to a transporter
protein assoc w/ Ag
processing (TAP)
TAP is a heterodimer
which uses ATP to help
transport peptides (8-10
aas) to lumen of ER
Usually basic aas @
COOH end of peptide
chain
MHC I assembly occurs w/ the
aid of chaperone proteins to
promote folding (calnexin +
MHC I chain)
Tapasin + calreticulin brings
TAP/ peptide close to MHC
assembly
Allows MHC I to bind to
peptides
MHC I-Ag exits ER to Golgi to
plasma membrane
Endogenous Ag processing
peptide binding to MHC I
Assembly and stabilization of MHC I Ag complex
Exogenous antigens
Exogenous antigens ( inhaled , ingested or injected ) are
taken up by APCs
MHC class II processing pathway

The Class II histocompatibility molecule consists of

Two transmembrane polypeptides
A third molecule nestled in the groove they form

All three components of this complex must be present in the
endoplasmic reticulum for proper assembly
But antigenic peptide are not transported to the endoplasmic
reticulum , so the protein is called invarient chain li
temporarily occupies the groove

Present on most immune system cells, specifically on APC (M, B-cells, DCs)


MHC class II processing pathway
Antigenic protein endosome/lysosome peptide
fragment
Newly synthesized class II molecules move to ER
and associate with invariant chain protein
molecule move to Golgi apparatus move to
endosomes/lysosomes release of invariant chain
from class II molecule class II binds antigenic
peptide fragment transport to cell surface
MHC class II processing pathway
The Steps:
The two chains of the class II molecule are inserted into the
membrane of the endoplasmic reticulum
They bind (in their groove) one molecule of in variant chain
This trimolecular complex is transported through the Golgi
apparatus and into vessicles called Lysosomes
Meanwhile,
Foreign antigenic material is engulfed by endocytosis forming
endosomes
These are fuse with lysosomes
Then,
The antigen is digested into fragments
The invariant (Li) chain is digested ( removed)
This frees the groove for occupancy by the antigenic fragment
The vesicle moves to the plasma membrane and the complex is
displayed at the cell surface

Endosome & lysosome
acidic protease & lysosome enzymes

Function
Degrade protein into peptide fragments (10-30
aa)

MHC calss II pathway
1. Capture and processing of exogenous Ag

2. Synthesis and transportation of MHC II molecules

3. Formation of peptide - MHC II molecule complex

4.Presentation of peptide - MHC II molecule complex
to CD4+ T cells


1. Capture and processing of exogenous Ag

Exogenous antigens are endocytosed and the endosome is
formed

endocytosis:
phagocytosis: particles or granules
pinocytosis: liquids
receptor-mediated endocytosis: specific exogenous
antigen

Endosome
A vesicle is formed by partial cell membrane which
surrounds the endocytosed antigens
Endosome
A vesicle is formed by partial cell membrane which surrounds the
endocytosed antigens

A phagolysome is formed when the endosome is fused with
lysosome

cathepsins
Ag antigen peptides

The antigen is hydrolysed into peptides by various proteases, such
as cathepsins.
2. Synthesis and transportation of MHC II molecules

Synthesis of MHC II molecules in ER

Ii chain interacts with the peptide-binding cleft of MHC II
molecule ,Preventing any peptides from combining with MHC
II molecules within ER
Ii leads MHC II molecules into endosome from ER via Golgi
complex

Endosome (MIIC)
3. Formation of peptide - MHC II molecule complex

The Ii in the Ii-MHC II molecules complex is degraded in endosome

protease Ii chain cleaving

CLIP remains bound to the MHC class II molecules ( CLIP-MHC II
molecules)
HLA-DM catalyzes the exchange of CLIP with antigenic peptides.

HLA-DM CLIP releasing

Antigen peptide-MHC II molecules


4.Presentation of peptide - MHC II molecule complex to
CD4+ T cells


antigen peptide-MHC II molecuels
presented on cell membrane by exocytosis
Processing of Exogenous Ags:
the Endocytic pathway
Exogenous Ags are typically phagocytized/
endocytized by M and APCs
Foreign Ag is degraded w/i endocytic vacuole of
endocytic pathway. The pathway includes:
Early endosomes (pH 6-6.5)
Late endosomes or endolysosome (pH 5-6)
Lysomes (pH 4.5 5)
Ag is degraded into 13-18 aa polypeptides which bind to
MHC II
Eventually endocytic vacuole returns to PM recycling
surface receptors

Processing of Exogenous Ags:
the Endocytic pathway
Processing of Exogenous Ags:
manufacture of MHC II
w/i ER, and chains of MHC II combine w/ a protein the invariant chain (Ii, CD74)
the IC binds to MHC @peptide binding cleft + then exits the ER to Golgi apparatus
as proteolytic activity continues, the IC is degraded to a small fragment (CLIP*)
another MHC II (HLA-DM (found in endosomes)) substitutes Ag for CLIP w/i lysosome
MHC II Ag complex is transported to the PM
*CLIP = class II associated invariant chain peptide
Comparison of Ag-processing pathways
Distinctions between MHC I and MHC II
Most cells (target cells) can
present Ag w/ MHC I to T
C
s
Nearly all nucleated cells infected
by MO/virus, or abnormal
proteins prod by cancer cells,
aging cells, or by allogeneic cells
from transplants
Assoc w/ MHC I requires
replication of foreign entity (i.e.,
abnormal protein synth) within
the target cell
Only APCs can present Ag w/
MHC II to THs
APCs are of 2 categories:
Professional APCs
Non-professional APCs
Assoc w/ MHC II does not
require replication of entity w/i
target cells
Phagocytosis is important in Ag-
processing

MHC I MHC II