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What is immune system tolerant to?

Immune system is tolerant to self (self-tolerance)

Immune system is tolerant to harmless antigens such food or environmental ag

Immune system is tolerant to commensal microbiota


What is immunological tolerance?

Immunological tolerance refers to the mechanisms by which lack of immunological reactivity is induced and maintained

Like immunity, tolerance is antigen specific (unlike immunosuppression)


How do T cells recognise antigens?

Through TCR

Express TCR/CD3 (plus CD4 or CD8)

Recognise self MHC
Recognise peptide ag


What is significant about the T cell repertoire regarding tolerance?

The primary repertoire of T cells (and B cells & BCRs) is enormous as a result of combinatorial diversity

This repertoire contains self-reactive TCRs (*) and yet a normal immune system does not exhibit self-reactivity (i.e. autoimmunity).


Where does T cell development initially take place?

Lymphoid progenitors migrate from the bone marrow to the thymus where they develop into mature T cells


Role of thymus in T cell differentiation

The thymus is absolutely required for the differentiation of immature precursor into mature T cells.
Children without thymus (Di-George syndrome) or mice lacking a thymus (nude mice) do not have mature T cells.


How does the thymus change with age?

The human thymus is fully developed before birth and increases in size during puberty

Thymus is most active in the young and it atrophies markedly with age

It progressively shrinks (fat replaces areas where thymocytes existed)


What happens to the thymus by age 30

Degeneration is complete by the age of 30, but residual thymic activity persists until advanced age

The reduced production of T-cells does not completely impair immunity. Once established the repertoire of the T-cells is long-lived


What is immunosenescence

immunosenescence : progressive deterioration of immune responses mainly associated with age


What happens to TCR genes in the thymus?

they undergo DNA rearrangement in thymus


Why is a mechanism for repertoire selection and self-tolerance needed?

Generation of the TcR repertoire involves many random mechanisms to allow diversity

The specificity of TcR in the immature repertoire is also random & will include cells with receptors that are:
1. Harmful - negatively selected
2. Useless - neglect
3. Useful - positively selected


Which cells will form the peripheral T cell pool?

Only cells that bear antigen receptor with appropriate affinity for the peptide presented in self MHC complexes complete their maturation and form the peripheral T cell pool

Naïve T cells
which are:
self MHC restricted
self tolerant


Where do most T cells die?

T cells mature in the thymus but most die there.
98% of cells die in the thymus without inducing any inflammation or any change in the size of the thymus.

Thymic macrophages phagocytose apoptotic thymocytes.
5x10^7 go in per day but only 2x10^6 leave


Where does T cell development occur?

T cell development occurs in defined thymic microenvironment

Thymic stroma (epithelial cells + connective tissue) provides the microenviroment for T cell development and selection


What are thymocytes associated with?

Thymocytes are intimately associated with epithelial cells as they develop in the thymus


What does the T cell screening system involve?

Discrete forms of selection
Positive selection and negative selection


Positive selection

Retention of thymocytes expressing TcR that are RESTRICTED in their recognition of antigen by
self MHC
i.e. selection of the USEFUL


Negative selection

Removal of thymocytes expressing TcR that either recognise self antigens presented by self MHC
i.e. selection of the HARMFUL


Steps of positive selection

T cells from bone marrow negative for CD4,CD8,TCR: double negative go into thymus

in thymus: somatic rearrangement of genes encoding for b and a chains of TCR and expression of both CD4 and CD8 (small non-dividing cortical thymocytes, short life-span).

Thymocytes express TCR
Thymocytes able to recognise self MHC expressed on the surface of cortical epithelial cells SURVIVE

Induction to survival, differentiation, maturation (long-lived cells).

Those who cannot, DIE (apoptosis by dendritic cells)


Central tolerance steps

Positive selection: MHC restriction, get rid of those that bind too weakly

Negative selection: tolerance induction - get rid of those that bind too strongly


What T cells does the thymus accept?

The thymus accepts T cells that fall into a narrow window of affinity for MHC molecules


Where do positive and negative selection occur?

Positive and negative selection occur in distinct thymic microenvironments after interaction with different types of thymic stromal cells

Positive - using cortical epithelial cell in cortex
Negative - using dendritic cells in cortico-medullary junction


How can the thymus express all self antigens – including self antigens only made by specialised tissues?

How do we become self tolerant to these antigens?

Transcription factor expressed at high levels by thymic medullary epithelial cells

Mutations of AIRE lead to autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED), also called autoimmune polyendocrine syndrome (APS-1)
Mouse knockout: failure to express many self antigens in the thymus and expression of autoantibodies


How is self-tolerance established to antigens that
cannot be expressed in the thymus?

T cells bearing TcR reactive with proteins expressed in the thymus are deleted.
Some self proteins are not expressed in the thymus e.g. antigens first expressed at puberty
Self tolerance needs to be induced and maintained outside the thymus



Peripheral tolerance

Tolerance to foreign antigens is induced and maintained in mature lymphocytes

Not all potential ‘self’ molecules are present in the thymus during TCR development
eg lactose, insulin, antigens first expressed at puberty etc etc ...

Don’t want to make an immune response against harmless things / food

Don’t want excessive lymphocyte activation and tissue damage during normal protective responses against infections

Auto-immunity/allergy - breakdown of peripheral tolerance: the immune system responds to self or environmental ag


mechanisms of peripheral tolerance

lymphocytes fail to recognise or respond

binding of ag makes lymphocyte unresponsive

continued stimulation by persistent antigen may ‘wear out’ responsive cells

interaction with other cells (or cytokines) may inhibit responsiveness


Clonal ignorance

self reactive lymphocytes fail to recognise or respond to some self antigens in the periphery
cells neither die nor become anergic


What is immune privilege?

Self -reactive T cells sometimes ignore ag

antigens anatomically sequestered from the immune system: T cells cannot reach cells bearing the ag
Tissue grafts placed in these sites are not rejected

immunologically privileged sites
(eye, testis, uterus/placenta)

if sequestred ag is released autoimmunity can result (many vasectomised males have anti-sperm Abs)


Eye as an immune-privileged site

Eye anterior chamber is an immune-privileged site. Normally, self-antigens in this site are not exposed to the immune system
Physical trauma in one eye can initiate autoimmune response to both eyes. This can cause blindness in the both damaged and undamaged eyes: Sympathetic ophthalmia


2. Induction of anergy

presentation without costimulation
CTLA-4 signaling

CD28 and CTLA-4 have opposing functions

Knockout of CTLA-4 in mice and heterozygous mutation in humans results in immune dysregulation (lymphoproliferation, multi-organ inflammation)