Mimm 314: Positive/negative Selection Of T-Cells

Front 1

Which T cells are positively selected for?

Back 1

T cells able to interact with self-MHC molecules

Front 2

Which T cells are negatively selected against?

Back 2

T cells that have too much affinity for self peptides/self-MHC complexes

Front 3

What happens when a mouse s irradiated?

Back 3

All lymphocytes and bone arrow progenitors of the recipient are destroyed
(All cells of hematopoietic origin die, all other cells are ok .: mouse can no longer make any hematopoeitic cells)

Front 4

How was positive selection demonstrated?

Back 4

Taking bone marrow cells from a mouse of of 1 MHC genotype and transferring them to an irradiated mouse of a different MHC genotype

Front 5

What happens when the bone marrow of one mouse is transferred to the irradiated mouse of a different MHC?

Back 5

Hemaopoirtic ells from the donor bone marrow will make progenitors and the recipient will have T and B cells
The MHC of the new hematopoietic cells will be of the donor

Front 6

What genotype do the radiant resistant cells (all the cells that are not of hematopoietic origin, includin non-lymphoid stromal thymus cells) express?

Back 6

MHC genotype of the recipient (the original genotype)

Front 7

What do cells of a mouse that has genotype MHC a x b express?

Back 7

BM cells: co-express a and b (co-dominant)
Other cells: only express a

Front 8

What happens once BM cells are transferred from the donor to the recipient?

Back 8

Mouse will be able to make B and T cells
-> These will express MHC of the DONOR on all hematopoietic cells

Front 9

What determines the restriction of the mature T cell repertoire?

Back 9

The MHC molecules expressed by the radio-resistant cells of the recipient

Front 10

What is the host component that is responsible for the positive selection of developing T cells?

Back 10

Thymic stroma

Front 11

What happens if all the cells in a mouse express MHC a x b, but the thymic graft injected into the mouse only contains MHCa?

Back 11

T-cells only respond to MHC a (.: Thymus directs MHC response)
MHC restriction of the mature T cell repertoire is determined by the Thymic Stroma in which they develop

Front 12

What kind of response is observed if all BM derived cells (including APCs) express the MHC of the donor (MHCa) but the other cells of the body, including stromal cells express the MHCb of the recipient?

Back 12

Only T-cells that recognize MHCb are selected for, but the APC in the periphery express only MHCa
.: T cells that are MHCb restricted can't recognize the MHC and Ag presented by their own APCs during an immune response
Levels of T-cell response will be very low

Front 13

When would there be a strong response?

Back 13

If MHCb APCs were ijected at the time of immunization with the BM
Will see immune responses restricted to MHCb

Front 14

What does immunizing mean?

Back 14

Injecting a foreign antigen into an animal to elicit an immune response

Front 15

LOOK at Positive selection table on page 4

Back 15

look at positive selection table on page 4

Front 16

What did generation of TCR transgenic mice show?

Back 16

Interaction of T cells with self-MHC:self peptide complexes is necessary for T cell development

Front 17

What happens when transgenes that contain rearranged α and β chain genes are introduced into mice?

Back 17

Inhibits rearrangement of endogenous α and β cain-genes (like BCR transgenic mice)

Front 18

hen will mice that have transgenes for a TCR made from MHCa-restricted T cell produce mature TCR-transgeinc T cells?

Back 18

If the stromal cells express MHCa
**Only thymocytes that express a TCR able to interact with self-MHC complexes can survive and mature**

Front 19

What happens if the stromal cells don't express MHCa?

Back 19

The thymocytes don't progress furthe than the DP stage and die in the thymus
->Absence of positive electon leads to cell death*

Front 20

What determines which co-receptor mature T cells will express?

Back 20

Specificity of the TCR for self MHC

Front 21

Which T cells mature?

Back 21

Only thjose that express a co-receptor that binds the same MHC molecules as the TCR

Front 22

What type of T cells will mature if the transgenic receptor recognizes MHC I? MHC II?

Back 22

MHC I: CD8+ T cells mature
MHC II: CD4+ T cells mature

Front 23

What if mice/humans are MHC II deficient? MHC I deficient?

Back 23

MHC II deficient: Have CD8+ T cells, but very few abnormal CD4+ T cells
MHC I deficient: Have CD4+ T cells, but very few, abnormal CD8+ T cells

Front 24

What is bare lymphocyte syndrome?

Back 24

Absence of MHC molecules in humans

Front 25

What does positive selection depend on?

Back 25

Engagement of both the TCR and to co-receptor with an MHC molecule

Front 26

What is one hypothesis that explains the lineage commitment of the T cells?

Back 26

lck (Src-family Tyr kinase) signals are most effectively delivered wjen CD4 rather than CD8 is engaged as a co-receptor

Front 27

Describe this hypothsis.

Back 27

Express both CD4 and 8 (DP)
Then downregulate expression of both
Then upregulate expression of CD4
-If the cell is selected by MHC II:
--> sustained signal mediated at in part by Lck.
-->Differentiation along the CD4 path and loss of CD8 expression
-If the cell is selected for by MHC I:
--> there was upreg'l of CD4, but no further signalling by Lck cuz CD4 is not ligated
-->Differentiation along the CD8 path
--> Loss of CD4 expression and upreg'l of CD8 expression
--> No induction of Th-POK TF

Front 28

Which thymic stromal cells mediate positive selection of developing thymocytes?

Back 28

The cortical epithelial cells

Front 29

What if a transgene MHC II molec is added but it can't bind to CD4?

Back 29

CD4+ T cells don't mature

Front 30

Where do most immature thymocytes enter the thymus through?

Back 30

The medulla and migrate through the cortex

Front 31

Where are DN4 cell found?

Back 31

Cortex

Front 32

Where does positive selection occur?

Back 32

Cortico-medullary junction (where mature CD4/CD8 cells will be generated)

Front 33

Where are most mature thymocytes found?

Back 33

In the medulla

Front 34

How do cortical epithelial cells mediate expression of all T-cells?

Back 34

They express both MHC I and II
(different from other epithelial cells that only express MHC I)

Front 35

What is negative selection?

Back 35

Kill immature T-cells if they hve too high affnity for a peptide

Front 36

What happened in the thymus of transgenic mice that carry a trangenic TCR for an ovalbumine peptide presented by an MHC II, after the ovalbumin peptide was injected in them?

Back 36

Mature T cells in the periphery become activated, while most of the T cells in the thymus die
(similar results in thymic organ culture)

Front 37

What happens in male mice that carry the transgene for the HY TCR? In female mice?

Back 37

In Male mice that carry the transgenes for this TCR, their transgenic thymocytes die at the DP stage and no mature transgenic T cells are found in the periphery
In female mice that carry transgenes for this TCR, the transgenic T cells mature normally because the female mice don't express the HY protein
**Thymocytes that arry a TCR specific for self-peptides/self-MHC molec are deleted n the thymus**

Front 38

What happens to tissue specific self Ag that are not expectd to be expressed in the thymus?

Back 38

Many tissue specific self Ag are expressed in the thymus
->Their expression is controlled by AIRE (autoimmune regulator)
*AIRE may not account for expression of all tissue-specific self-Ags

Front 39

Wher is AIRE expressed?

Back 39

By stromal cells in the medulla

Front 40

What happens if AIRE is mutated?

Back 40

Autoimmune disease: autoimmune plyglandular syndrome type I

Front 41

When can negative selection occur?

Back 41

Throughout T cell development, in the thymic cortex and medulla

Front 42

Which cell types in the thymus can mediate negative selection?

Back 42

Many different types
**Most important: Macrophages and dendritic cells**
They cn induce tolerance to a different MHC class if they express it, even if the thymic cells express a different MHC

Front 43

Can thymic epithelial cells mediate negative selection?

Back 43

Yes, they can too

Front 44

When do thymocytes migrate to peripheral organs?

Back 44

at the SP stage
(Only small amount of mature thymocytes are xported to the periphery: 1-2 x 10^6/day, unlike with B cells)

Front 45

What is required for T ecll survival in the periphery?

Back 45

Cst contact with self-peptides/MHC complexes: these are encountered n the lymphoid subset of interdigitating dendritic cells in the T-cel zone of lymphoid organs
-Also need Cytokines: IL-7