Development of T lymphocytes

Question 1

Double negative

Answer 1

When they do not express any co receptors (thymic immigrant stage)

Question 2

Double positive

Answer 2

Both co receptors are expressed

Question 3

Single positive

Answer 3

Only 1 co receptor is expressed

Question 4

T cells

Answer 4

• derive from bone marrow stem cells
• rearrange TCR genes in the thymus (antigen independent)
• formation of 2 different T cell lineages (majority alpha/beta, and minority gamma/delta)
• positive selection (alpha/beta)
• negative selection (gamma/delta)

Question 5

B cells

Answer 5

• derive from bone marrow stem cells
• rearrange BCR genes in the BM (antigen independent)
• somatic hypermutation (antigen dependent)

Question 6

Thymus

Answer 6

Primary lymphoid organ

• T cell development only
• blood is only route to enter (T cell progenitors) and to leave (mature T cells)

Question 7

Hassall’s corpuscle

Answer 7

Site of cell destruction, located in the medulla of the thymus

Question 8

Differences between canine and human thymus

Answer 8

There are none

Question 9

2 types of thymus epithelial cells

Answer 9

• cortical (thymicorigin)

- medullary (thymicorigin)

Question 10

Other cells presented in the thymus

Answer 10

• thymocyte (bone marrow origin)
• dendritic cell (bone marrow origin)
• macrophage (bone marrow origin)

Question 11

Thymus development

Answer 11

• most active in very young
• fully developed at birth
• atrophies with increasing age, thymocytes replaced by fat (involution)
• involution complete by 30 years

Question 12

Does involution or a thymectomy compromise T cell immunity?

Answer 12

No, T cells are long lived or self-renewing

Question 13

Thymus involution

Answer 13

DiGeorge’s syndrome

• thymus fails to develop = SCIDS
• 22q11.2 deletion syndrome

Question 14

Thymic cortex

Answer 14

• apoptotic cells

- macrophages

Question 15

A common double negative T cell progenitor gives rise to _______

Answer 15

Alpha/beta and gamma/delta T cells

Question 16

2 major signals for T cell lineage commitment

Answer 16

• IL-7

- Notch 1

Question 17

CD34

Answer 17

Uncommitted progenitor

Question 18

CD2

Answer 18

Committed double-negative T cell progenitor

Question 19

Gamma + delta

Answer 19

Committed gamma/delta T cell

Question 20

Beta lineage

Answer 20

Uncommitted double-positive thymocyte

• CD8 and CD4 receptors
• first checkpoint

Question 21

Alpha + beta

Answer 21

Committed alpha/beta T cell

• CD8 and CD4 receptors expressed
• second checkpoint
• study chart in ppt*

Question 22

Positive selection

Answer 22

Selection of T cells that can recognize peptides presented by a self-MHC molecule

• small population of T cells is signaled to mature further, leaving majority of double positive cells to die by apoptosis
• controls expression of CD4 or CD8 co receptor

Question 23

Negative selection

Answer 23

Deletion of T cells whose antigen receptors bind too strongly to the complexes of self-peptides and self- MHC molecules presented
- negative selection cannot eliminate T cells whose receptors are specific for self peptides that are present only in tissues other than the thymus

Question 24

Negative selection

Answer 24

Deletion of T cells whose antigen receptors bind too strongly to the complexes of self-peptides and self- MHC molecules presented
- negative selection cannot eliminate T cells whose receptors are specific for self peptides that are present only in tissues other than the thymus

Question 25

AIRE

Answer 25

Autoimmune regulator - mutation causes autoimmune polyglandular syndrome type 1 or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) - Because of AIRE gene, APCs in the thymus express and present many peptides derived from nonthymic tissues

Question 26

What happens if there are only thymus specific cells in the thymus?

Answer 26

T cells will go to periphery and be autoreactive | - AIRE gene is the safety mechanism

Question 27

What is the major mechanism of immunological tolerance in the thymus?

Answer 27

Negative selection

Question 28

Thymic epithelial cells and transcription factor

Answer 28

Transcription factor causes several hundred of other tissue specific genes to be transcribed by a subpopulation of the thymic epithelial cells

Question 29

Mechanisms that contribute to immunological self-tolerance

Answer 29

Central tolerance - negative selection in the bone marrow and thymus - expression of tissue-specific proteins in the thymus (AIRE) Peripheral tolerance - no lymphocyte access to some tissues - suppression of autoimmune responses by regulatory T cells - induction of anergy in autoreactive B and T cells (absence of co stimulatory signal)

Question 30

Mechanisms of malignant transformations and generation of lymphomas

Answer 30

- high division rate of maturing lymphocytes | - activity of DNA recombination mechanisms responsible for generating antigen receptor diversity

Question 31

Terminally differentiated T cells retain lifelong capacity for _____

Answer 31

Neoplasia

Question 32

Canine X-linked SCIDS

Answer 32

<4 weeks: greater number of B cells and CD45RA + T cells >8 weeks: increased B cells and T cells, decreased CD45RA+T cells

Question 33

XLSCID in Basset Hounds

Answer 33

Cell counts: dramatically fewer T cells, but normal or above number if IgM B cells

Question 34

Immunological analysis

Answer 34

- roles of IL-2 in T cell proliferation in the thymus and proliferation and differentiation in the secondary lymphoid organs - roles of IL-4 in differentiation of B and Th2 cells - roles of IL-7 in the development of lymphoid progenitor cells in the bone marrow

Question 35

Explanation of clinical evidence

Answer 35

Explains severe atrophy of both primary and secondary lymphoid organs and absence of mature B cells - does not explain the elevated numbers of T cells at the age of 8 weeks

Question 36

What are the 3 functionally distinct types of T cell developed from a common progenitor in the thymus?

Answer 36

- gamma/delta T cells (not MHC restricted) - alpha/beta CD4+ T cells (MHC 2 restricted) - alpha/beta CD8+ T cells (MHC 1 restricted)

Question 37

Subsequent phases in the thymus only concern _____

Answer 37

Alpha/beta T cells

Question 38

Positive selection tests the ability of ______ to interact with ____ expressed in the thymus

Answer 38

Alpha/beta TCRs; self-MHC molecules

Question 39

Negative selection eliminates cells whose ________

Answer 39

Receptors interact too strongly with self-peptide; self MHC complexes

Question 40

Main difference between thymus and bone marrow

Answer 40

Bone marrow continuously turns of B cell repertoire during the person's lifetime, while the thymus works principally during youth to accumulate a repertoire of T cells that can be used throughout life * reflects magnitude of body's investment in development of useful T cells and savings to be made by gradually shutting down the thymus *