T Cell tolerance Flashcards
What is tolerance and where can it occur?
- lack of responsiveness to self
- occurs in thymus (central tolerance) and in the tissues (peripheral tolerance)
What is a tolerogenic antigen?
-one that a T cell binds and drives it towards unresponsiveness (anergy) or even death
3 general outcomes of T cell encounters with antigens
- activation
- tolerance
- ignorance
Usually placing skin graft from breed Y into Z is rejected, but what if the Z recipient was newborn?
-it would accept it because the IS is still developing and learning what is self and nonself
Negative selection occurs in the thymus to eliminate overactive T cells, but what about antigens that never make their way into the thymus? What process accounts for this and what are the 3 different categories of it?
- peripheral tolerance
1. lack of co-stimulation
2. regulatory (suppressive) T cells
3. Activation-induced cell death
What happens if a resting APC binds with peptide to a T cell?
-tolerogenic response because resting APC won’t have B7 that is needed to activate a naive T cell
Explain how CTLA4 can be used to make transplants across major MHC differences succeed.
-soluble CTLA4 will bind all of the available B7 and thus block T cell activation and transplant rejection
2 actions of Tregs
- production of inhibitory cytokines that block T cell effector functions
- interfering directly in T cell activation
Compare immunogenic vs. tolerogenic antigens on their presence in generative organs, presentation with second signals, and persistance
- T:present in generative organs for central tolerance; not presented with second signals (anergy or apoptosis); long-lived
- I: not in generative organs (peripheral); present with second signal to promote lymphocyte survival and activation; usually short lived
T/F: Central tolerance typically results in anergic T cells.
- false; results in clonal deletion
- remember, negative selection occurs in thymus which ends in apoptosis!!!
Why does it make sense that tolerogenic antigens are NOT presented with co-stimulatory signals?
-tolerance is the end result of only receiving signal 1!!! if you received both signals, you would activate a T cell population against that antigen which is the opposite of tolerance
Define central tolerance and peripheral tolerance.
- central tolerance refers to elimination of self-reactive lymphocytes during their development; clonal deletion
- peripheral tolerance refers to suppression of immune responses by cells that, although self-reactive, have escaped deletion during development
Activation-induced cell death: what is it? what signals it?
- stimulated T cells are eliminated by apoptosis after immunogenic challenge has been met
- apoptosis occurs following engagement of a cell surface receptor (Fas/CD95) expressed on ACTIVATED T cells
- can also occur due to unbalanced pro and anti-apoptotic proteins
How does Fas signalling work?
- activated a protease cascade resulting in DNA fragmentation and cell death
- death receptor!!!
- when activated, T cells upregulate Fas and FasL and once challenge is met, these link together and induce apoptosis in eachother
Describe T cell levels before and after antigen exposure to naive T cell
-have more after the fact and these are due to creation of memory cells
Descriptive mechanism of Fas/FasL
- bind at cell surface and trimerize
- conformational change in Fas occurs, when then binds death domain-containing adaptor proteins
- cascade to turn on caspase 3 which will fragment DNA
Define autoimmunity
- when tolerance is broken or when activated T cells fail to be eliminated, effector T cells may respond to self antigen leading to pathophysiology
- may result from failed central or peripheral tolerance
Generally, autoimmunity results from a combination of what factors?
-genetic (particular MHC/HLA alleles and genes outside of MHC complex) and environmental (inflammation or infection with microbes)
2 ways of developing autoimmunity
- induction of costimulators on APCs: stimulated APCs express costimulators. By chance, these APCs also may interact with a T cell with potential self-reactivity; self reactive T cell will expand
- Molecular mimicry: an APC presents engulfed microbe that happens to resemble a self-antigen; when these T cells expand and encounter the similar self-antigen, autoimmunity results
Failure of T cell activation will lead to ___________. Failure of appropriate T cell death may lead to _____________. Dysregulation of T cell selection may lead to ________________.
- immunodeficiency
- lymphoproliferative and/or autoimmune disorders
- autoimmunity
T cell issues associated with autoimmune and immunodeficient diseases
SCID can result from the failure of T cells to develop or defects in T cell activation. Name 3 things that can happen due to loss of T cells?
- interferes with B cell function since T cell help is required for optimal B cell activity
- interfere with some macrophage activities
- interferes with cytolysis of infected host cells
affects T and B cells
Autoimmune lymphoproliferative syndrome
- defects in Fas signaling lead to impaired peripheral T cell apoptosis
- expanded T cell populations fail to be eliminated resulting in lymphadenopathy and splenomegaly
- persisting activated T cells may lead to autoimmunity
Autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED)
- rare autoimmune disorder characterized by involvement of multiple tissues
- caused by genetic abnormality in AIRE gene
What do AIRE defects result in?
- failed presentation of self antigen in thymus, leading to maturation of autoreactive T cells that injure tissues when they escape to the periphery
- failure of clonal deletion in thymus
How does one block TCR activation at its most proximal level? How does one stop cytokine production? How does one block T cell proliferation?
- block TCR with monoclonal antibodies
- block calcineurin function with prevents NFAT entry into nucleus
- Block IL-2 R and signaling pathways
