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
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
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
IGNORANCE:
lymphocytes fail to recognise or respond
CLONAL ANERGY:
binding of ag makes lymphocyte unresponsive
CLONAL EXAUSTION:
continued stimulation by persistent antigen may ‘wear out’ responsive cells
SUPPRESSION:
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
- 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)
Therapeutic application of CTLA-4
Blocking CTLA-4 promotes tumor rejection
CTLA-4 limits immune responses to tumors
Administration of antibody that blocks CTLA-4 in
tumor-bearing mouse leads to tumor regression
Anti-CTLA-4 antibody is approved for tumor immunotherapy (enhancing immune responses against tumors)
Even more impressive results with anti-PD-1 in cancer patients
Activation-induced cell death (AICD)
Repeated stimulation of T lymphocytes by persistent antigens results in death by apoptosis of the activated cell
Elimination of T cells specific for abundant peripheral antigens: Clonal exhaustion (expression of inhibitory receptors on exhausted T cells, e.g. CTLA-4, PD-1)
suppression
Treg cells are critical components in the maintenance of peripheral tolerance through “suppressive” mechanisms
Tregs suppress the activation of effector responses and are critical for regulating homeostasis and tolerance to self antigens
Treg deficiency
Deficiency of T regulatory cells is associated with aggressive autoimmunity IPEX [Immunodysregulation, Polyendocrinopathy and Enteropathy, X-linked syndrome]: fatal autoimmune disorder characterised by systemic autoimmunity in the first year of life
Treg clinical application
Critical role of Treg in promoting tolerance
may be exploited to:
strengthen or re-establish self-tolerance
in autoimmune disease
induce tolerance to non-self-antigens
in organ transplantation, GVHD and allergy
Induce tumour immunity in cancer patients
What determines whether an antigen is tolerogenic or immunogenic
the same antigen can be
tolerogenic or immunogenic,
depending on how/when/where it is encountered
How the antigen is presented to lymphocytes:
concentration
timing
persistence
tissue distribution
nature of the cell presenting the antigen
How the responses of specific lymphocytes to that antigen are regulated
Antigen properties
Molecular weight
Smaller, soluble, not-aggregated molecules favors tolerance
large, aggregated, complex molecules favors immunogenicity
Dosage
very small or large favors tolerance
intermediate favors immunogenicity
Routes of administration
Oral, intratracheal, orbital exposure can activate T cells to secrete TGFbeta (Tregs).
Oral tolerance
Interaction of food proteins with gut-associated lymphoid tissue (GALT) in the intestinal transit is the essential prerequisite for oral tolerance.
Different cells of the immune system participate in oral tolerance induction, with regulatory T cells being the most important.
Clinical applications of oral tolerance
clinical trials :
Disease Antigen Multiple Sclerosis (MS) Myelin Basic Protein (MPB)
Rheumatoid Arthritis (RA) Type II collagen
Type I Diabetes Insulin
Hyposensitisation ImmunotherapyOral immunotheraphy (OIT)
using small amount of allergens (food, pollen) to induce antigen specific tolerance
continuous administration of the allergen, rather than its elimination, to promote the development and maintenance of tolerance
Oral/sublingual desensitisation immunotherapy for peanut allergy holds promise for the control of allergy
Note: Sensitization to food antigen can occur through cutaneous exposure!
