Immune recognition and immune tolerance Flashcards
Main cellular players in immune response
Innate:
-Dendritic cells
-Macrophages
-Neutrophils
Adaptive:
-CD4+ helper T cells
-CD8+ cytotoxic T cells
-B cells
Downside of random T cell receptor diversity
-Self reactivity is possible
-Autoimmune conditions
What does immune tolerance allow?
-Prevents autoreactivity but permits appropriate anti-pathogen responses
How do T cells develop
-Develop in the thymus gland
-T cell precursors are seeded from bone marrow into thymus
-Multi-lobular organ containing
organised zones with several specialized cell types
What is thymic education of T cells?
-Thymocytes from bone marrow are seeded into thymus, where they express functional T cell receptor
-Learn which accessory molecule (CD4+ or CD8+) is more appropriate for that T cell
-Learn how to use them safely & within the laws of MHC restriction
What happens to T cells that can’t express a functional T cell receptor
-Only T cells capable of forming alpha beta T cell receptor survive
-Cells with non-functional T cell receptor die by apoptosis
How do T cells positively select for self MHC
-Thymic cortex presents MHC I and II
-If T cell has affinity for MHC II, it stops expressing CD8+ and will graduate as a CD4+ receptor
-If T cell has affinity for MHC I, it stops expressing CD4+ and will graduate as a CD8+ receptor
-Some T cells don’t have affinity for MHC I or II - they apoptose and die
What is negative selection of T cells
-Eliminates high affinity self-reactive T cells
-T cells with high affinity for self peptide and self MHC are eliminated
-T cells with low/moderate affinity are allowed to graduate
-Takes place in Thymic Medullary Epithelial cells (TMECs)
What Tissue Restricted Antigens (TRAs) do Thymic Medullary Epithelial Cells (TMECs) express?
What can failure of TRA expression lead to?
-Failure of Thymic Medullary Epithelial Cells (TMECs) to express tissue restricted antigens leads to
autoimmune diseases
E.g. Autoimmune Polyglandular Syndrome type 1
Thymic education flow chart
What are the 2 peripheral mechanisms of immune tolerance
-Anergy
-Regulatory T cells
What is anergy?
-Signal 1 without signal 2 causes anergy
-Anergy is when T cells remain in circulation but are unresponsive to future stimulation
-Anergy occurs under steady state conditions: when not activated by infection/inflammation, APC do not express co-stimulatory molecules
3 reasons why anergy is important?
-Important for tolerance to antigens
not expressed in thymus
-Important for tolerance to food antigens
-Important for tolerance to commensal bacteria
What are regulatory T cells and how do they work?
-T cells dedicated to controlling or suppressing effector T cells
-Directly alter function of effector T cells to stop them proliferating/secreting cytokines
-Reduce costimulation and alter cytokine production by APCs to stop messages getting to effector T cells
What are the 2 main types of regulatory T cells?
nTreg:
-‘naturally occurring’
-Produced in thymus
-Respond to self antigens
-Protection for autoimmunity
aTreg:
-‘adaptive, i.e. induced’
-Develop in periphery
-Constant low level exposure to antigen
-Protection from autoimmunity
-Regulation of responses to food antigens
T regs and autoimmune diseases
-Individuals lacking nTreg develop multiple autoimmune diseases
-Individuals with autoimmune diseases often have impaired Treg function
-Tregs are targeted in immunotherapy of autoimmune diseases
2 methods to prevent function of Tregs?
-anti- tumour responses
-vaccination
PAMPs and PRRs
-Tissue dwelling APC recognise bacterial/viral products as
‘foreign’ via pathogen associated molecular patterns (PAMPs)
-PAMPs are conserved products of microbial metabolism which are:
-unique to microbes
-invariant between members of a given class
-vital for microbial fitness
-Immune system has a range of pattern recognition receptors (PRRs) which recognise PAMPs
Where and how does activation of naive lymphocytes occur?
-Lymphoid organs
-Here they secrete combination of cytokines and chemokines which lead to upregulation of adhesion molecules on the high endothelial venules that line the arterioles going into the lymph node
-This, along with the chemokines leads to increase of naive T cell migration into lymph node
-Signals which allow T cells to leave lymph node are blocked
-Causing increase in size and cellularity of lymph node -inflammation
What is signal 3 in this image?
-Cytokine production by dendritic cell that instructs T cell to polarise into the type of T cell that is good at clearing the bacterial infection
Differentiation of CD4+ T helper cells
What happens when T cells encounter inflamed tissue?
-Cross over from bloodstream into tissue
-CD4+ T cells will secrete cytokines (IFN-y, TNF-A) which help neutrophils and macrophages clear pathogens
-CD8+ T cells will kill cells that present peptide on MHC I
-Some T cells migrate out of tissue and become memory cells
What happens when infection is removed?
-the innate system is no longer activated - inflammation subsides
-antigen is cleared - the stimulus for T cells is removed
-most effector T and B are removed - death by neglect/cytokine
starvation
-apoptotic cells are removed by macrophages
