11 B and T cell development and differentiation Flashcards
what must be ensured in B and T cell development
do not respond to self-antigen (negative selection)
what must be ensured in T development
T cells can respond to MHC (positive selection)
what are the different receptors on the T cell surface
CD4 and CD8
Lymphocyte binding repertoire
Because of the myriad of microbial challenges-antigen binding repertoire has to be extensive
Self-binding must occur during the process of the generation of diversity
why is there mechanisms to minimise lymphocyte binding repertoire
devastating consequences (i.e. autoimmunity)
what are the two tolerance to self
Central Tolerance
Peripheral Tolerance
what does central Tolerance concern
immature T and B cells at the point of differentiation where
Central Tolerance effect
> B cells have a newly former Ig at surface forming a BCR
> Pre-T cells differentiate intoCD4and CD8
Central Tolerance - mechanisms
> clonal deletion or inactivation of the cell
> wide range of self-antigens expressed in primary lymphoid tissue to aid this process
what does peripheral Tolerance relate to
mature T cells after they have left the primary lymphoid tissue
Peripheral Tolerance effects
> Clonal deletion and anergy but others too e.g. suppression
> Antigens expressed in tissues
B cells develop in bone marrow then migrate to lymphoid tissues
bone marrow
Immature B-cells proliferate
Differentiate and develop antigen receptors (surface Ig)
Self-reactive cells eliminated
Bone marrow stromal cells (i.e. connective tissues) interact and provide factors (cytokines) necessary for development to eliminate self-reactive cells
what do B cells need to be able to function
- Encounter antigen
- Recognise it
- Respond to it
- Differentiate - effector cell
Recognise it - B cells
> As the B-cell only has one immunoglobulin receptor it can recognise
Therefore, there is only going to be a few antigens that B cell will recognise
Respond to it - B cells
> response driven by support given to B cell in secondary lymphoid organs
B cell tolerance
If the B cell receptor on the immature B cell detects antigens in the bone marrow it is deleted
when are B cells made
produced throughout your life
why is there a need for mechanisms to stop self recognition in B cells
As gene rearrangement occurs (which defines the antigen specificity) there is a need for mechanism to stop self recognition
what does an immature B cell express
surface IgM
what does a mature B cell express
surface IgD+ IgM
how do B cells generate in the bone marrow
B cell precursor rearranges immunoglobulin genes
what happens in negative selection in the bone marrow
immature B cell bound to self cell surface antigen is removed from repertoire
when do B cells migrate to the peripheral lymphoid organs
mature B cell bound to foreign antigen is activated
how are plasma and memory cells
activated b cells give rise to plasma cells and memory cells
antibody secretion in bone marrow and lymphoid tissue and memory cells in lymphoid tissue
what do the outcomes of developmental routes for B cell depend on
4 possible outcomes for a B cell which depend on the types and strength of interactions with antigens in the bone marrow
Developmental routes for B cell
4 possible outcomes
- Deletion
- Receptor editing
- Anergy
- Mature B cell
what happens if during B cell development recognises self
- Recognises self antigens
- Deletion (very strong binding)
- Receptor editing (but v early in development process)
- Anergy (if it is a weak binding – leads to suppression of cells)
what happens if B cell does not recognise self antigens
Mature B cell
B cell DELETION
multivalent ligands have to be bound
- Use anti-IgM experimentally - cells die by apoptosis
As a mature B cell is activated by the same ligands - this process only works before they mature
- B cell is now expressing IgD on their surface
what does immature B cell express
IgM
RECEPTOR EDITING
If IgM is bound by antigen in bone marrow immediate elimination (deletion) is NOT the only outcome
Cell can produce a new receptor by editing existing light chain gene
There is an interval between antigen recognition and apoptosis where cell can be rescued
effect of receptor editing
results in deletion or displacement of old light chain gene with a new one
INACTIVATION (Anergic)
If the immature B cell encounters monovalent molecule the cell is inactivated (ANERGIC)
These cells lose their expression of surface IgM
Mainly express IgD, but are released from bone marrow
Peripheral Tolerance silencing
There is a need to silence cells in the periphery e.g. to liver/kidney antigens
Cells can be deleted or anergised (made silent)
valency of antigens
- Multivalent
- Monovalent
multivalent
(several sites at which attachment to antigen can occur) = able to be deleted in the periphery
monovalent
(one site at which attachment to antigen can occur) = able to be made anergic (silent)
where does clonal deletion occur
in bone marrow or periphery
where does anergy occur
in bone marrow or periphery
Thymus
Bi-lobed organ which sits above the heart
2 compartments-cortex and medulla
thymus cortex
Cortex-outer compartment has densely packed immature thymocytes (proliferate here) 95-99% will die
thymus medulla
more sparsely populated-subset of mature thymocytes on the way out
what is within the thymus
stromal cell network-epithelial cells, dendritic cells and macrophages interact with thymocytes
what do thymic epithelial cells form
network around developing thymocytes
Role of Thymus - Thymectomize
dramatic reduction in T cells
DiGeorges syndrome (humans) in mice
nude mice -born with no thymus –no T cells
Scid mice defect
have thymus but lymphocyte defect-no T cells
Bone marrow stem cells from nude mouse gives T cell progenitors
So transplanted T cell progenitors can use the normal thymus to develop fully
Nude mouse
No thymus but normal T cell progenitors
Thymic architecture from SCID mouse gives a site for T cell progenitors to develop
SO existing T cell progenitors can use transplanted thymus to develop fully
Maturation of T cells effect
T cells mature the antigenic diversity of capability to recognise ag occurs by random mutation
what happens to maturing T cells
- As they express Ag binding receptors (T cell receptor) selection occurs
- Cells positively selected by recognising self MHC (on epithelial cells of thymus)
- Negatively selected if recognise self in MHC
how do T cell progenitors develop in bone marrow and migrate to the thymus
T cell precursor rearranges its T cell receptor genes in thymus
what happens in positive and negative selection in thymus
immature T cells that recognises self MHC receive signals for survival
those that interact strongly with self antigen are removed from repertoire
when do mature T cells migrate to the the peripheral lymphoid organs
mature T cells encounter foreign antigens in the peripheral lymphoid organs and are activated
when do activated T cells migrate to sites of inflammation
activatedT cells proliferate and migrate to peripheral sites to eliminate infection
where do most cells die
in the thymus
what happens to single positive cells
exported to the periphery from the thymus
when do T cell Surface markers change
change during development
what happens when cells enter thymus-negative
Proliferate and express CD-2 but CD4 and CD8 negative
- “double negatives”
what are the double positive cells where are they exported to
CD4+8- and CD4-8+ exported to periphery
Need to recognise self MHC
1st Phase is positive selection where cells that recognise self MHC peptide complex are selected for survival this happens on double positive cells
If TCR does not recognise self MHC it will die by programmed cell death
Positive selection
Not only selects for MHC reactive cells Also co-ordinates the expression of CD4 or CD8 thus determining the type of effector function Initially expresses both CD4 and CD8 Selection based on whether react to class I or class II MHC in thymus
why do CD4 and CD8 cells require different programming
different effector functions
what are cortical epithelial cells needed for
cells are critical for positive selection
what do cortical epithelial cells make close contact to
developing thymocytes
when are CD8+ T cell matured
transgenic receptor recognises MHC class 1 immature CD4+8+ double-positive T cells
when are CD4+ T cell matured
transgenic receptor recognises MHC class 2 Immature CD4+8+ double positive T cells
Peptides in MHC affect positive selection
Ensures developing T cells have TCR which doesn’t react to self-antigens from rest of body
But T cells have to have TCR which will interact with self MHC
Delicate balance of affinity
why are many self peptides expressed in thymus
due to the action of the AIRE (autoimmune regulator protein)
NEGATIVE SELECTION
If T cell encounters Antigen in the thymus it DIES
- many self antigens expressed either from circulation or thymus itself
what can demonstrate negative selection
Male ag can demonstrate this
Transgenic mouse with TCR for male antigens
Key question How can MHC peptide/TCR ligation lead to BOTH positive and negative selection
2 hypotheses
- Avidity –i.e the strength of the binding and no receptors engaged
- Differential signalling-i.e nature of the signal different
what is needed for a reaction
Bottom line is need 2 signals, TCR plus co-stimulation
Co stimulatory alone
MHC alone
They’re not enough on own need both
what happens if only co stimulatory or MHC alone
No second signal = anergy
