Major Histocompatibility Complex (MHC) and T Cell Development

Question 1

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

Answer 1

MHC Locus

Question 2

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

Answer 2

Major histocompatibility antigens

Question 3

The MHC complex in humans is called

Answer 3

Human Leukocyte Antigen (HLA)

Question 4

The MHC in the mouse is called

Answer 4

H-2

Question 5

MHC antigens are divided into which two types?

Answer 5

Class I and Class II

Question 6

Both classes of MHC antigens are

Answer 6

Heterodimers

Question 7

The most polymorphic genes of the human MHC. The ones that are routinely matched in pre-transplantation testing

Answer 7

Genes A, B, and DR

Question 8

Made of a polymorphic alpha chain and a non-polymorphic beta chain called B2-microglobulin

Answer 8

Class I antigens

Question 9

Made of polymorphic alpha and beta chains

Answer 9

Class II antigens

Question 10

These proteins belong to the immunoglobulin superfamily and have similar domain structures

Answer 10

Class I and II antigens

Question 11

Remember that MHC nomenclature is

Answer 11

Case sensitive

Question 12

The mouse MHC locus (H-2) contains three polymorphic class-I genes encoding three class I alpha chain genes called

Answer 12

K, D, and L

Question 13

The mouse MHC locus (H-2) contains 4 genes encoding two a and two B class two chains, which make the

Answer 13

A and E class II antigens

Question 14

The murine MHC locus is located on chromosome

Answer 14

17

Question 15

The human MHC (HLA) is similar in structure to the murine H-2 and encodes three class I antigens called

Answer 15

A, B, and C

Question 16

The human MHC (HLA) encodes three class II antigens called

Answer 16

DP, DQ, and DR

Question 17

The class II region also contains which 4 non-polymorphic class II genes

Answer 17

DM, DO, LMP, and TAP genes

Question 18

The human MHC is located on chromosome

Answer 18

6

Question 19

Not part of the MHC and is located on chromosome 15 in humans and 2 in mice

Answer 19

B2-microglobulin

Question 20

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

Answer 20

MHC Class III genes

Question 21

The particular combination of MHC alleles on a chromosome is called an

Answer 21

MHC Haplotype

Question 22

In mice all members of an inbred stain would, by definition, have the same haplotype which is designated by a small letter such as

Answer 22

b, d, k, or q (remember, casesensitive!)

Question 23

Strains in which the endogenous MHC is replaced by an entire MHC locus from another strain

Answer 23

Congenic strains

Question 24

A congenic strain in which the H-2d from the DBA/2 strain was introduced into the a B10 mouse

Answer 24

B10.D2

Question 25

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

Answer 25

Recombinant strains

Question 26

Expressed on all cells in the body

Answer 26

MHC class I antigens

Question 27

Normally expressed only on antigen presenting cells (APC)

Answer 27

MHC Class II antigens

Question 28

Which three types of cells express the most class II antigens?

Answer 28

B cells, Dendritic Cells, and thymic epithelium

Question 29

Do not express Class II, brain microglia, of the monocyte/macrophage lineage, do

Answer 29

Neurons

Question 30

Recognize viral antigens in virus-infected cells only as a complex with MHC antigens

Answer 30

T Cells

Question 31

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

Answer 31

MHC haplotype

Question 32

The ability of T cells to recognize a particular MHC as self depends on the MHC haplotype(s) present in the

Answer 32

Thymus when they mature

Question 33

Most cytotoxic cells express the T cell marker

Answer 33

CD8

Question 34

Helper T cells always express the T cell marker

Answer 34

CD4

Question 35

Cells expressing CD4 antigen always recognize antigens in the context of

Answer 35

MHC Class II antigens

Question 36

Always recognize antigen in the context of MHC class I antigens

Answer 36

CD8 T cells

Question 37

Can only recognize a mutation on self MHC class I antigens

Answer 37

CD8 T cells

Question 38

Can only recognize a mutation on self MHC class II antigens

Answer 38

CD4 T cells

Question 39

Restricted by Class I molecules of the MHC

Answer 39

Hapten-specific CTL's

Question 40

A congenic strain in which the normal MHC haplotype d of strain B10 has been replaced with haplotype k

Answer 40

B10.DR

Question 41

A recombinant strain whose MHC is derived from haplotypes s, k, and d

Answer 41

AT.L

Question 42

Engraftment experiments showed that T cell restriction occurred in vivo and was imposed by the MHC haplotype present in the thymus in which the

Answer 42

T cell was produced

Question 43

A x B TH that mature in a strain B thymus will only recognize antigen when it is presented by

Answer 43

APC of strain B

Question 44

A x B CTL that mature in a Strain A thymus will kill virus-infected cells of

Answer 44

Strain A but not Strain B

Question 45

T cells will only ‘help’ B cells of the same

Answer 45

MHC type

Question 46

Specifically bind to MHC class II and MHC class I molecules respectively

Answer 46

CD4 and CD8 molecules

Question 47

Binding determines the Class of MHC recognized by a T cell

Answer 47

T cell

Question 48

Although CD4+ cells can sometimes function as CTL, they will always be restricted by (= recognize antigen bound to)

Answer 48

MHC class II

Question 49

Antigens originating outside of the cell (like bacterial and other extracellular pathogens) are presented as a complex with -only expressed on antigen presenting cells

Answer 49

MHC class II

Question 50

Antigens originating within the cell (like viral and tumor antigens) are presented as a complex with

Answer 50

MHC class I

Question 51

Some antigens can “cross” between the two pathways and will be then presented on both

Answer 51

Class I and Class II molecules

Question 52

For example, viral antigens which are mostly presented by MHC class I molecules can also end up in endosomes and be processed for

Answer 52

MHC class II presentation

Question 53

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

Answer 53

Pathogens

Question 54

Most bacteria are extracellular and T cell help will be required for antibody production and will therefore be processed for

Answer 54

MHC class II

Question 55

Viruses on the other hand reside inside cells, where antibody cannot reach them. To kill the infected cell, they require

Answer 55

Cytotoxic T Lymphocytes (CTL's)

Question 56

TH recognize exogenous antigen which is phagocytosed and presented by Class II. CTL recognize antigen synthesized inside cells, which is presented by

Answer 56

Class I

Question 57

Cleaves antigens into fragments

Answer 57

Proteosome

Question 58

Transports the fragments to the lumen of the rough ER, where they bind to newly made Class I

Answer 58

Transport of Antigenic Peptides (TAP) system

Question 59

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

Answer 59

MHC class I antigens

Question 60

No MHC means no

Answer 60

Immune recognition

Question 61

All other immune responses are tightly regulated such that the initiation of antigen specific reactions is controlled by specialized cells called the

Answer 61

APC

Question 62

The APC expresses

Answer 62

Class II antigens

Question 63

Obviously, a certain MHC haplotype will not bind all possible peptides processed for

Answer 63

Presentation

Question 64

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

Answer 64

Pathogens

Question 65

Successful T cell activation requires, in addition to the recognition of antigen/MHC, the presence of co-stimulatory molecules on

Answer 65

APC

Question 66

These molecules on APC bind to specific ligands expressed on

Answer 66

T cells

Question 67

The main molecules of this type of the APC are

Answer 67

B7-1 and B7-2

Question 68

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

Answer 68

Anergy

Question 69

CD4+ cells can be further divided into which two subtypes based on their cytokine secretion profile and on their immune functions?

Answer 69

Th1 (inflammatory) and Th2 (helper)

Question 70

The thymus is essential for the development of

Answer 70

T cells

Question 71

Very few T cells migrate out of the

Answer 71

Thymus

Question 72

Development of monoclonal antibodies specific for particular TCR families supplied the first clue for what happens during

Answer 72

Thymic selection

Question 73

T cells that recognize self antigens are not allowed to exit the thymus and are eliminated by a process termed

Answer 73

Negative selection

Question 74

The thymic selection process was elegantly demonstrated in experiments using

Answer 74

TCR transgenic mice

Question 75

For teaching purposes, we will accept the “theoretical truth” that a rearranged TCR will prevent any further rearrangements of other

Answer 75

TCR genes (= “allelic exclusion”)

Question 76

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

Answer 76

MHC class I of the b haplotype

Question 77

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

Answer 77

CD8+

Question 78

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

Answer 78

Self

Question 79

They are thus eliminated by

Answer 79

Negative selection

Question 80

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

Answer 80

Thymus

Question 81

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

Answer 81

Positive selection

Question 82

Only cells with TCR that match self MHC, at least with some affinity, are allowed to mature further

Answer 82

Positive selection

Question 83

The reason for positive selection is that in a mouse antigens are presented only by -because there is no other MHC available

Answer 83

Self MHC

Question 84

So if a Tcell has a receptor that does not ‘match’ self MHC, that cell is

Answer 84

Useless

Question 85

T cells of irrelevant specificity are not only useless, but present a

Answer 85

Risk

Question 86

Secondary lymphoid organs will become large, swollen with huge numbers of useless

Answer 86

T cells

Question 87

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

Answer 87

Denis Lo experiment

Question 88

In the Denis Lo experiment. What was found in 1. ) H-2b mice? 2. ) H-2s mice?

Answer 88

1. ) Only CD8+ and no CD4+ | 2. ) No CD8+ or CD4+

Question 89

In homozygous H-2b mice positive selection takes place, since the clone that was the source of the TCR transgenes was positivelyselected by

Answer 89

H-2b MHC

Question 90

This positive selection will only operate on

Answer 90

CD8+ cells

Question 91

No CD4+ cells will form since there is no positive selection for them, because the TCR specificity is for

Answer 91

Class I

Question 92

Since the clone came from an H-2b mouse CD8+ cells escape negative selection by

Answer 92

H-2b mice

Question 93

In b x s mice the same things happen since a single b haplotype suffices for

Answer 93

Positive selection

Question 94

In b x d mice there will also be positive selection but now negative selection will also occur since

Answer 94

Ld is present

Question 95

In homozygous H-2s mice there will be no positive selection: the receptor specificity requires the

Answer 95

H-2b haplotype for positive selection

Question 96

Two processes, during maturation in the thymus, determine the final T cell repertoire in the adult. This was a conclusion from the

Answer 96

Denis Lo experiment

Question 97

Allows only T cells that recognize self MHC to develop further

Answer 97

Positive Selection

Question 98

Removes T cells that show a dangerously high reactivity towards self

Answer 98

Negative selection

Question 99

The crucial factor is the affinity of the developing thymocyte for

Answer 99

Self MHC + Self antigens

Question 100

On one hand, T cells that recognize self antigens with high affinity can become autoreactive and cause

Answer 100

Autoimmune disease

Question 101

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

Answer 101

Mature

Question 102

This is why only a few percent of T cells formed in the thymus are allowed to

Answer 102

Leave it

Question 103

The set of foreign antigens encountered determines which immature T cells will make -the "third-round" of selection

Answer 103

Immune responses