9. Mechanisms of tolerance Flashcards
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:
- Harmful - negatively selected
- Useless - neglect
- 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 and 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
