Central and Peripheral tolerance

Immunologic tolerance

unresponsiveness to an antigen that is induced by a previous exposure to that antigen

Central tolerance

Thymus (T cell)

Bone marrow (B cell)

Peripheral tolerance

Adenoids (GALT)

Tonsils (GALT)

Peyer’s patches (GALT)

Appendix (GALT)

Central tolerance n

Development of Tregs - a goldilocks zone

What happens if T reg is deleted?

Tregs are selected from thymocytes that bind moderately to self antigen present on MHC class II. This affinity is stronger than conventional T cells (survive positive selection) but not strong enough to trigger deletion via negative selection

If T reg is deleted, autoimmunity is induced

AIRE

Autoimmune regulator

Interacts with transcription proteins which enable some tissue-specific proteins to be expressed in the thymus

ectopic expression of tissue-specific antigens

AIRE creates an immunological show of the peripheral self in the medullary thyroid epithelial cells

APECED - autoimmune polyendocrinopathy candidasis ectodermal dystrophy

Patients that are defective in AIRE and develop autoimmunity

What are the 4 mechanisms of peripheral tolerance?

• Clonal deletion

• Clonal anergy

• Ignorance (barriers)

• Regulation (Treg involved)

1. Clonal deletion (apoptosis)

T cells that recognise self antigens without inflammation or are repeatedly stimulated by antigens are triggered to die by apoptosis

Major mechanism for CD4+ cells is via activation of the death receptor Fas - due to the ligan FasL

Die by apoptosis due to the lack of stimulatory molecule

2. Clonal anergy (functional unresponsiveness)

Antigen presented inappropriately

Absence of second co-stimulatory signal

Or may involve the presence of an inhibitory receptor CTLA-4

Even in the presence of co stimulatory signal, the inhibitory receptor on the T cell - CTLA4 upregulating binds to B7 on the APC

CTLA-4 has an ITIM motif cytoplasmically

CLTA-4 blocks CD28 - B7 interaction, as well as pulling B7 away from the APC, which further induces the lack of co-stimulation

→ T cell unresponsiveness

3. Ignorance

Antigens are sequestered in organs that are not accessible to the immune systm

There is a physical barrier between the self-antigen and the lymhoid system

eg Blood brain barrier

Testis

Anterior chamber of the eye

Example: sympathetic opthalmia

Trauma to one eye results in the release of sequestered intraocular protein antigens that are usually physically privilege - the release of these antigens are carried to lymph nodes and activates T cells, which leads to effector T cell activity that attacks the antigen on both eyes.

4. Regulation

Active suppression involving regulatory T cells

Antigen specific

Extremely potent effect

Where are T regs generated?

• Natural T regs are generated by the recognition of self antigen in the thymus (central tolerance)

• Inducible T regs - generated by recognition in the peripheral lymphoid organs

  All have the same peripheral functions

Treg properties

They are CD4+

CD25 HIGH - T regs do not produce IL2 themselves, but they depend on it for survival .By expressing high CD25, they outcompetes effector T cells for IL-2 which limit effector expansion.

They express FoxP3 transcription factor: FoxP3 is a specific marker for T regs which binds to promoter region and regulate Treg functions

Both CD25 and FoxP3 are crucial for T cell function

Function of Tregs

1. Inhibits effector T cell activation by expressing high level of CTLA-4

2. Production of IL-10 and TGF-b which are inhibitory cytokines which dampen down the inflammatory environment.

What is the proportion of CD4+ T cells that are T regs in normal environment vs in a tumour?

Normally T regs make up ~4% circulating CD4+ T cells

In tumour microenvironment T regs can make up 20-30%

Central tolerance in B cells - 4 fates

1. No self reactivity: BCR does not recognise self-antigen in the bone marrow, which passes the checkpoint and mature normally

2. Strong binding to multivalent self—antigen

• Multivalent antigens crosslink multiple BCRs,which triggers strong signalling: clonal deletion via apoptosis, or receptor editing via surface expression of IgM decrease and RAG expression maintained for the production and expression of new light chain

• If the new receptor is not self reactive, the cell can be rescued

3. Binding to soluble seft antigen without cross-linking: these B cells migrate to the periphery but are functionally unrsponsive and anergic - fal to activate to re-exposed to antigen

4. BCR binds self antign weakly and monovalently with minimal signaling: B cells migrate to the periphery and can be controlled by peripheral tolerance mechanisms.

Peripheral tolerance in B cells

B cells that recognise self-antigens in the absence of T cell help die by apoptosis or becomes anergic

CD22 has intracellular ITIM , act as inhibitor for B cells that recognise self antigens with low affinity