Major Histocompatibility Complex (MHC) and T Cell Development Flashcards
Discovered in the early 1900s by tumor biologists who noticed that tumors arising in a particular inbred strain of mice could be transplanted into mice of the same inbred strain but not to mice of other inbred strains
MHC Locus
Further genetic studies revealed that the rejection of transplanted tumors as well as normal tissues is governed mostly by one set of cell surface antigens which were termed
Major histocompatibility antigens
The MHC complex in humans is called
Human Leukocyte Antigen (HLA)
The MHC in the mouse is called
H-2
MHC antigens are divided into which two types?
Class I and Class II
Both classes of MHC antigens are
Heterodimers
The most polymorphic genes of the human MHC. The ones that are routinely matched in pre-transplantation testing
Genes A, B, and DR
Made of a polymorphic alpha chain and a non-polymorphic beta chain called B2-microglobulin
Class I antigens
Made of polymorphic alpha and beta chains
Class II antigens
These proteins belong to the immunoglobulin superfamily and have similar domain structures
Class I and II antigens
Remember that MHC nomenclature is
Case sensitive
The mouse MHC locus (H-2) contains three polymorphic class-I genes encoding three class I alpha chain genes called
K, D, and L
The mouse MHC locus (H-2) contains 4 genes encoding two a and two B class two chains, which make the
A and E class II antigens
The murine MHC locus is located on chromosome
17
The human MHC (HLA) is similar in structure to the murine H-2 and encodes three class I antigens called
A, B, and C
The human MHC (HLA) encodes three class II antigens called
DP, DQ, and DR
The class II region also contains which 4 non-polymorphic class II genes
DM, DO, LMP, and TAP genes
The human MHC is located on chromosome
6
Not part of the MHC and is located on chromosome 15 in humans and 2 in mice
B2-microglobulin
The MHC locus in all species contains other genes some of which are related to antigen processing and MHC-peptide complex formation and some are totally unrelated to the function of MHC. These unrelated genes, as a group, are called
MHC Class III genes
The particular combination of MHC alleles on a chromosome is called an
MHC Haplotype
In mice all members of an inbred stain would, by definition, have the same haplotype which is designated by a small letter such as
b, d, k, or q (remember, casesensitive!)
Strains in which the endogenous MHC is replaced by an entire MHC locus from another strain
Congenic strains
A congenic strain in which the H-2d from the DBA/2 strain was introduced into the a B10 mouse
B10.D2
Strains in which only a portion of the endogenous MHC complex has been replaced by MHC of another haplotype, by breeding from one strain into another
Recombinant strains
Expressed on all cells in the body
MHC class I antigens
Normally expressed only on antigen presenting cells (APC)
MHC Class II antigens
Which three types of cells express the most class II antigens?
B cells, Dendritic Cells, and thymic epithelium
Do not express Class II, brain microglia, of the monocyte/macrophage lineage, do
Neurons
Recognize viral antigens in virus-infected cells only as a complex with MHC antigens
T Cells
In an experiment, T cells ‘primed’ by exposure to a virus in a particular mouse strain could only recognize and kill virus-infected cells of the same
MHC haplotype
The ability of T cells to recognize a particular MHC as self depends on the MHC haplotype(s) present in the
Thymus when they mature
Most cytotoxic cells express the T cell marker
CD8
Helper T cells always express the T cell marker
CD4
Cells expressing CD4 antigen always recognize antigens in the context of
MHC Class II antigens
Always recognize antigen in the context of MHC class I antigens
CD8 T cells
Can only recognize a mutation on self MHC class I antigens
CD8 T cells
Can only recognize a mutation on self MHC class II antigens
CD4 T cells
Restricted by Class I molecules of the MHC
Hapten-specific CTL’s
A congenic strain in which the normal MHC haplotype d of strain B10 has been replaced with haplotype k
B10.DR
A recombinant strain whose MHC is derived from haplotypes s, k, and d
AT.L
Engraftment experiments showed that T cell restriction occurred in vivo and was imposed by the MHC haplotype present in the thymus in which the
T cell was produced
A x B TH that mature in a strain B thymus will only recognize antigen when it is presented by
APC of strain B
A x B CTL that mature in a Strain A thymus will kill virus-infected cells of
Strain A but not Strain B
T cells will only ‘help’ B cells of the same
MHC type
Specifically bind to MHC class II and MHC class I molecules respectively
CD4 and CD8 molecules
Binding determines the Class of MHC recognized by a T cell
T cell
Although CD4+ cells can sometimes function as CTL, they will always be restricted by (= recognize antigen bound to)
MHC class II
Antigens originating outside of the cell (like bacterial and other extracellular pathogens) are presented as a complex with
-only expressed on antigen presenting cells
MHC class II
Antigens originating within the cell (like viral and tumor antigens) are presented as a complex with
MHC class I
Some antigens can “cross” between the two pathways and will be then presented on both
Class I and Class II molecules
For example, viral antigens which are mostly presented by MHC class I molecules can also end up in endosomes and be processed for
MHC class II presentation
The physiological importance of having two antigen presenting pathways, which lead to two different types of immune responses, is to ensure proper immune reactions to different types of
Pathogens
Most bacteria are extracellular and T cell help will be required for antibody production and will therefore be processed for
MHC class II
Viruses on the other hand reside inside cells, where antibody cannot reach them. To kill the infected cell, they require
Cytotoxic T Lymphocytes (CTL’s)
TH recognize exogenous antigen which is phagocytosed and presented by Class II. CTL recognize antigen synthesized inside cells, which is presented by
Class I
Cleaves antigens into fragments
Proteosome
Transports the fragments to the lumen of the rough ER, where they bind to newly made Class I
Transport of Antigenic Peptides (TAP) system
Obviously, the immune system has to be able to get rid of all virus infected cells and therefore all cells in the body must express
MHC class I antigens
No MHC means no
Immune recognition
All other immune responses are tightly regulated such that the initiation of antigen specific reactions is controlled by specialized cells called the
APC
The APC expresses
Class II antigens
Obviously, a certain MHC haplotype will not bind all possible peptides processed for
Presentation
However, it is highly unlikely that NONE of the peptides processed from a particular viral or bacterial proteins will bind to a particular MHC haplotype therefore ensuring an immune response to practically all
Pathogens
Successful T cell activation requires, in addition to the recognition of antigen/MHC, the presence of co-stimulatory molecules on
APC
These molecules on APC bind to specific ligands expressed on
T cells
The main molecules of this type of the APC are
B7-1 and B7-2
Engagement of the T cell receptor (TCR) in the absence of costimulatory molecules leads to a state of antigen-specific unresponsiveness often referred to as
Anergy
CD4+ cells can be further divided into which two subtypes based on their cytokine secretion profile and on their immune functions?
Th1 (inflammatory) and Th2 (helper)
The thymus is essential for the development of
T cells
Very few T cells migrate out of the
Thymus
Development of monoclonal antibodies specific for particular TCR families supplied the first clue for what happens during
Thymic selection
T cells that recognize self antigens are not allowed to exit the thymus and are eliminated by a process termed
Negative selection
The thymic selection process was elegantly demonstrated in experiments using
TCR transgenic mice
For teaching purposes, we will accept the “theoretical truth” that a rearranged TCR will prevent any further rearrangements of other
TCR genes (= “allelic exclusion”)
In both experiments summarized below, the TCR was molecularly cloned from a CD8+ CTL clone originating from an H-2b mouse, which means that the TCR recognizes antigen in the context of
MHC class I of the b haplotype
In the Herald von Boehmer experiment, all T cells recognize H-Y peptides bound to H-2b Class I MHC. T-cells which carry receptors of this specificity are
CD8+
In male mice, H-Y peptides are present. Immature cells in the thymus which recognize H-Y/H-2b Class I MHC are dangerous because they recognize
Self
They are thus eliminated by
Negative selection
In the HvB experiment, in female mice H-Y peptides are not present, so these cells are not dangerous and are allowed to survive and leave the
Thymus
The lack of CD4+ in both males and female in the HvB experiment showed that there is another form of selection in the thymus called
Positive selection
Only cells with TCR that match self MHC, at least with some affinity, are allowed to mature further
Positive selection
The reason for positive selection is that in a mouse antigens are presented only by
-because there is no other MHC available
Self MHC
So if a Tcell has a receptor that does not ‘match’ self MHC, that cell is
Useless
T cells of irrelevant specificity are not only useless, but present a
Risk
Secondary lymphoid organs will become large, swollen with huge numbers of useless
T cells
CTL cloned from an H-2b mouse with receptor specificity anti-Ld. The TCR genes were cloned and transgenic mice made carrying different types of MHC
Denis Lo experiment
In the Denis Lo experiment. What was found in
- ) H-2b mice?
- ) H-2s mice?
- ) Only CD8+ and no CD4+
2. ) No CD8+ or CD4+
In homozygous H-2b mice positive selection takes place, since the clone that was the source of the TCR transgenes was positivelyselected by
H-2b MHC
This positive selection will only operate on
CD8+ cells
No CD4+ cells will form since there is no positive selection for them, because the TCR specificity is for
Class I
Since the clone came from an H-2b mouse CD8+ cells escape negative selection by
H-2b mice
In b x s mice the same things happen since a single b haplotype suffices for
Positive selection
In b x d mice there will also be positive selection but now negative selection will also occur since
Ld is present
In homozygous H-2s mice there will be no positive selection: the receptor specificity requires the
H-2b haplotype for positive selection
Two processes, during maturation in the thymus, determine the final T cell repertoire in the adult. This was a conclusion from the
Denis Lo experiment
Allows only T cells that recognize self MHC to develop further
Positive Selection
Removes T cells that show a dangerously high reactivity towards self
Negative selection
The crucial factor is the affinity of the developing thymocyte for
Self MHC + Self antigens
On one hand, T cells that recognize self antigens with high affinity can become autoreactive and cause
Autoimmune disease
Only T cells that recognize self MHC in a narrow range of affinity (high enough to be useful, low enough not to be dangerous) are allowed to
Mature
This is why only a few percent of T cells formed in the thymus are allowed to
Leave it
The set of foreign antigens encountered determines which immature T cells will make
-the “third-round” of selection
Immune responses
