Fig 12-5
Overview of the two pathways from your textbook
Left hand side is the endogenous pathway. This could be going on
in all cell types in your body. A protein in the cytosol is broken
down by the ubiquitin-proteosome pathway (see next slide), and the
peptide fragments generated are transported into the ER by a
transporter system called TAP (transporter associated with antigen
processing or transporter of antigenic peptides). In the lumen of
the ER are newly synthesized MHC class I proteins getting ready to
head to the cell surface. If they can bind one of the peptides they
will and take it out to the surface. In the absence of a peptide
the class I molecule is unstable and wont make it to the
surface.
Right hand side is the exogenous pathway. This would be going on
in professional Ag presenting cells such as macrophages. Exogenous
antigens, such as a bacterium, are phagocytosed and broken down in
the lysosomes. A newly synthesized class II molecule is transported
in a vesicle that fuses with the lysosome allowing the class II to
pick up any peptides generated and take them to the surface for
presentation. The invariant chain is an auxiliary protein that
plays the role of a mock peptide to keep the class II stable until
it has the opportunity to pick up a real antigen.Pre-T cells enter
the thymus in the cortical region and progressively move towards
the medullary region as they mature. They all start out as double
negative (DN) cells which means they have neither CD4 nor CD8 on
their surface. The first decision a cell makes is to be either an
ab or a gd cell, referring to which TCR to rearrange.
Cells that become gd T cells, leave the thymus and remain DN.
The role of these cells remains unclear and the possibilities will
be discussed later. Cells that become ab cells first change from DN
to double positive (DP), expressing both CD4 and CD8. The cell then
undergoes its first selection, called positive selection. Cells are
tested for the ability of their TCR to bind to self MHC, class I or
II. Those cells whose receptor binds class II become CD4 cells
ultimatel, those that bind class I become CD8 cells. Those that
came up with a TCR that can bind neither fail positive selection
and die via apoptosis. The second round of selection is negative
selection. Those cells that have a TCR that binds MHC molecules
with self peptides with high affinity are also killed by apoptosis.
This is the primary mechanism by which self tolerance is maintained
my eliminating T cells that have a high affinity receptor for MHC
plus self peptide. Once the cells complete both rounds of selection
they become single positive (SP) for either CD4 or CD8
Overview of the two pathways from your textbook
Left hand side is the endogenous pathway. This could be going on
in all cell types in your body. A protein in the cytosol is broken
down by the ubiquitin-proteosome pathway (see next slide), and the
peptide fragments generated are transported into the ER by a
transporter system called TAP (transporter associated with antigen
processing or transporter of antigenic peptides). In the lumen of
the ER are newly synthesized MHC class I proteins getting ready to
head to the cell surface. If they can bind one of the peptides they
will and take it out to the surface. In the absence of a peptide
the class I molecule is unstable and wont make it to the
surface.
Right hand side is the exogenous pathway. This would be going on
in professional Ag presenting cells such as macrophages. Exogenous
antigens, such as a bacterium, are phagocytosed and broken down in
the lysosomes. A newly synthesized class II molecule is transported
in a vesicle that fuses with the lysosome allowing the class II to
pick up any peptides generated and take them to the surface for
presentation. The invariant chain is an auxiliary protein that
plays the role of a mock peptide to keep the class II stable until
it has the opportunity to pick up a real antigen.NK cells have
receptors on their surface that can bind class I molecules. At
least two different kinds of receptors have evolved, one type based
on a C-type lectin structure, the other using Ig domains. Not all
species have both. Mice only have the C-type lectin form for
example.
Binding MHC class I with the KIR or Ly49 or CD94 receptor on the
NK cell shuts off the NK cell. This signal will override any other
activating signal and the NK cell will not kill. In the absence of
class I the target cell is killed.
What are the activating receptors (AR) and their ligand is still
being worked out. They must exist to tell the NK cell that there is
a target cell there. Right?
Activation by failing to bind MHC class I explains why they are
not MHC restricted. Right?
