Lymphocyte Production and Primary Lymphoid Organs + Tolerance

Question 1

What is the concept of tolerance and how does the need for it arise?

Answer 1

• T cells and B cells express specific receptors for antigen
• cell has capacity to produce a specific receptor independently to the influence of antigen
• inevitably, some cells would produce antibodies (B cells) or be cytolytic (T cells) to our own tissues
• the concept of tolerance is the set of mechanisms which prevent organisms from responding to self-constituents
• The process of eliminating or neutralising self-reactive lymphocytes is called tolerance

Question 2

Tolerance is a mechanism solely demonstrated by the immature immune system.
TRUE or FALSE

Answer 2

FALSE

• tolerance can be induced when the immune system is still immature
• it can also occur in the adult
• e.g. in pregnancy the mother does not reject the foreign paternally derived proteins expressed on the developing embryo

Question 3

What is central tolerance?

Answer 3

the mechanism that lead to lymphocyte tolerance of self that occur in the primary lymphoid organs (thymus and bone marrow)

Question 4

Which constraint on T cell recognition provides the basis for the key mechanisms of self-tolerance that operate within the thymus

Answer 4

B cells recognise native antigen
T cells only recognise fragmented peptides derived from an antigen. when these are presented in the cleft of a self-derived MHC molecule

Question 5

Why are T cells called T cells?

Answer 5

Their precursors are produced in the bone marrow but the development and selection of mature immunologically competent T cells occurs in the thymus

Question 6

The majority of T cells express a form of the TCR consisting of …… and ….. chains.
These cells are subject to two major selection processes in the thymus.
A second population of express a TCR consisting of …. and …. chains. Many of these cells develop within the thymus but some evidence not so

Answer 6

alpha and beta

gamma and delta

Question 7

Describe the gross and micro anatomy of the thymus gland

Answer 7

• encapsulated gland
• organised into lobules by capsular septa
• within each lobule there exists a complex meshwork of epithelial and other cells which regulate development of immature thymocytes
• thymic stromal cells + cells of haemopoietic origin
• stromal cells include thymic cortical epithelial cells, thymic medullary epithelial cells, dendritic cells

Question 8

TRUE or FALSE

The thymus gland shrinks with age and T cell lymphopoesis only occurs up to adolescence

Answer 8

FALSE
The thymus gland does shrink with age
It is largest and most active from the neonatal to adolescent period
By the early teens, the thymus begins to regress and thymic stroma is replaced by adipose tissue
Despite this, T cell lymphopoesis continues through adult life

Question 9

What are the different in cell type found in the cortex and medulla of thymus?

Answer 9

immature thymocytes = CORTEX

mature thymocytes = MEDULLA

Question 10

TCR’s are generated are generated by gene rearrangement - similar to generation of immunoglobulins.
When do these events occur?

Answer 10

They occur as the cells pass through the thymic cortex into the medulla

Question 11

The Cortex:

• What time of selection takes place here?
• What is the predominant stromal cell type? What do they do?
• What are the immature thymocytes here characterised by?

Answer 11

• positive selection
• reticular epithelial cells, form a network of fine processes, characterised by high expression of MHC II. Within this framework immature thymocytes lie here.
• characterised by co-expression of CD4 and CD8 molecules

Question 12

What is the boundary between the cortex and medulla called?
What is it populated by?
What is their function?
What is the second important cel type here?
What is their function?

Answer 12

cortico-medullary junction
macrophages - prevent damged for dying cells from passing into the medulla
dendrinitc cell - playa a key role in negative selection in the thymus

Question 13

The Medulla:

• Thymocytes that reach the medulla have undergone successful ….. …… ……….., …….. selection and a limited degree of ………… selection
• For what function is the medulla specialised?
• What are the predominant thymocyte subsets in the medulla?

Answer 13

• TCR gene rearrangement
  postive
  negative
• to allow thymocytes to undergo additional rounds of negative selection to remove T cells that recognise self-antigen
• CD4+8- and CD4-8+. which leave the thymus populate the periphery

Question 14

What is the AIRE gene?

What is it expressed by?

Answer 14

• Expressed by thymic epithelial cells (TECs)
• Autoimmune Regulator Gene
• Results in transcription of organ specific genes to allow maturing thyomcutes to be exposed to tissue specific antigen prior to being released into the circulation

Question 15

What are the two selection processes that immature alphabeta TCR bearing CD4+8+ thymocytes are subject to?

Answer 15

• positive selection

- negative selection

Question 16

What is positive selection?

What else happens at this stage of selection?

Answer 16

• cortical epithelial cells impose positive selection on differentiating thymocytes
• thymocytes which can recognise MHC are selected or permitted to continue their differentiation
• cells which fail to recognise MHC on epithelial cells re not selected and die by NEGLET
• During this stage of selection, T cells that recognise self MHC Class II molecules lose expression of CD8 and those recognising Class I molecules los expression of CD4

Question 17

What is negative selection?

Answer 17

• removes potentially dangerous T cells that recognise self-peptides
• thought to be mediated by dendritic cells

Question 18

What are the 4 distinct mechanisms that have been identified to contribute to self-tolerance in the periphery?

Answer 18

• ignorance
• regulatory T cells
• inappropriate antigen presentation
• threshold responses

Question 19

Describe ignorance

Answer 19

• several sites (e.g. eye/testis) sites of immune privilege
• mechanisms for this include immune suppression by cytokines such as TGF-beta, active deletion of reactive cells
• Also, immune system not truly tolerant to insides of cells
• If apoptotic mechanisms are compromised, the consequences are severe

Question 20

Describe the function of regulatory T cells

Answer 20

• these suppress effects of other T cells and other components of immune system, including antibody formation
• leave thymus shortly after birth
• prevent self-reactive T cells from mounting damaging immune responses

Question 21

What are regulatory T cells known to express?

Answer 21

CD4
alpha chain of IL-2 receptor
Foxp3

Question 22

Describe inappropriate antigen presentation

Answer 22

• In normal immune response the dendritic cell activate antigen specific T cells by presenting antigen but also provide additional ‘danger’ signals which ilfience the way in which primed T cells differentiate.
• Self protein fail to give these ‘danger’ signals. and although the self reactive T cell might recognise self antigens presented, it does not become activated
• helps to explain failure of foreign proteins expressed by embryo to be rejected by mother

Question 23

What mechanism is in place to make sure that most tissues cannot present their own proteins directly to CD4 cells, and therefore increased likelihood of autoimmunity?

Answer 23

CD4 cell only recognises antigens associated with MHC II molecules.
The expression of MHC II is restricted to dendritic cells, macrophages and B cells.

Question 24

Describe threshold responses

Answer 24

• T cells have the capacity to regulate themselves
• important gene cluster = T cell associated proteins CD28 and CTLA-4
• provide positive and negative cell activation signals respectively
• This allowed T cells to be activated and expanded rapidly but also be switched off
• If the brake is removed then males develop severe autoimmune disease as they cannot regulate their CD28-driven T cell responses

Question 25

Describe what is known about B cell tolerance

Answer 25

• no selection process equivalent to that of T cells
• however, if B cells encounter antigen before they reach secondary lymphoid tissue, they are either inactivated or deleted
• this diminishes self-responses, but also means that specific B cels produced within bone marrow during the course of an ongoing response are also likely to be lost
• major source of B cell tolerance is lack of T cell help
• B cells that encounter antigen in secondary lymphoid tissue require T cell help mount an effective antibody and memory response
• if the antigen is self-derived, such T cell help is unlikely