L5: T Cells Flashcards
How do Th cells and CTLs ‘see’ antigens?
Through their TCR (very polymorphic)
A T cell receptor is non-covalently associated with how many other proteins?
5 other proteins, to form a CD3 protein complex
What is CD3 involved in?
Signal transduction following recognition of its antigen
What are the components of the ‘tri-molecular complex’
TCR, antigen, MHC
Viral proteins are degraded to peptides and loaded onto which MHC class molecules?
Class I
(this alerts the immune system of infection)
APCs load short peptide antigens from the killed pathogen onto which MHC class molecules?
Class II
(they are then presented to TCR on Th cells)
MHC Class I antigens are typically recognised by which T cells?
CD8+ cytotoxic T cells (CTLs)
MHC Class II antigens are typically recognised by which T cells?
CD4+ T helper cells
Where do immature thymocytes mature into Th cells and CTLs?
the thymus
Why is the maintenance of immune response to ‘self’ in the thymus essential?
to prevent untoward immune responses and autoimmunity
What is the purpose of thymic education of thymocytes to naive T cells?
to eliminate any T cells that could potentially attack our own cells/tissues i.e. self-antigens
What are the 4 main cell types involved in the process of antigen presentation to maturing thymocytes?
Interdigitating dendritic cells
Thymic medullary epithelial cells (mTECs)
Cortical epithelial cells
Macrophages
Thymocytes are derived from…
lymphoid stem cells
99% of mature thymocytes have…
an αβTCR, the remainder have a 𝛾𝛿TCR
Where are 𝛾𝛿TCRs mainly found?
in the gut mucosa
Briefly explain the thymocyte maturation stages
- βTCR chain rearranges, CD3 in cytoplasm
- ~80% of thymocytes at any one time (double positives), CD1+ (homing marker), CD4+ CD8+ co-expression, αTCR chain rearranges, low density surface expression
- thymic education takes place, mature thymocytes are now CD1- and either CD4+ or CD8+ (single positives), high density surface expression of αβTCR
What happens in positive selection?
‘Dual recognition’ of (i) functional TCR (on T cell surface) and (ii) ability to recognise MHC molecules on the surface of an APC
What happens in negative selection?
The deletion of ‘self-reacting’ T cells
(if a TCR is autoreactive, it is killed by APCs via apoptosis and the apoptotic bodies are removed by macrophages)
What does the chemokine CCL25 do?
attracts progenitors to the thymus
How do thymic nurse cells support thymocyte proliferation?
by producing IL-7
What happens when single positive thymocytes leave the thymus?
They become naive effector T cells (Teff cells)
What is Aire?
a transcription factor that is highly expressed in mTECs and promotes the expression of 1000s of TSAs
What happens when developing thymocytes interact with TSAs?
negative selection of these thymocytes
True or False: Each mTEC will randomly express a given TSA gene.
True
Aire-induced TSAs in mTECs are expressed as orders of magnitude lower or higher than their expression in peripheral tissues?
Lower (you don’t want a large amount of these proteins made in mTECs)
Studies suggest that the capacity of Aire to regulate expression of a huge array of TSAs relies solely on…
unconventional transcriptional mechanisms, without intermediary transcription factors
Many additional proteins have been identified that assist Aire to recognise target TSAs by…
releasing stalled RNA polymerase to allow RNA elongation
(these proteins also regulate Aire itself)
What is the repressive epigenetic marker that is recognised by Aire?
unmethylated histone 3 lysine 4 (H3K4)
How does Aire appear different to other transcription factors?
Aire does not have a clear DNA binding motif but instead recognises genes that possess silenced/repressed chromatin states
What happens to the thymus after 40 years of age?
begins to involute and turn to fatty tissue, greatly reduces in size
What is the loss of thymic TECs associated with?
thymic atrophy and reductions in thymopoiesis
The expression of which TF in TECs decreases with age?
FoxN1
(causing rapid depletion of TECs)
What thymocyte-promoting factors are reduced in TECs with age?
IL-7 and MHCII
Does thymic involution occur faster in males or females?
Males
(role for androgens in thymic atrophy?)
What are Tregs essential for?
the maintenance of immunological self-tolerance and homeostasis
What does a thymectomy lead to?
inflammation and severe organ-specific autoimmune pathogenesis
What do loss-of-function mutations in the FoxP3 gene cause?
IPEX syndrome in humans
(spontaneous development of severe autoimmunity in mice)
What transcription factors promote IL-2 transcription?
NFAT, NF-κβ, AP-1
What are the roles of IL-2?
- stimulates production of other cytokines by T cells & APCs
- promotes B cell maturation
- promotes CTL/NK cell killing
- crucial for growth & maintenance of FoxP3 Tregs, and stable FoxP3 expression
- CD4+ and CD8+ cell proliferation and growth
- promotes apoptosis in antigen-activated T cells at the end of an infection
- optimal development, survival and function of Tregs
What are Tregs positive for?
CD4, CD25, FoxP3
Tregs are essential for?
(i) Limiting the activity of Teffs during proinflammatory responses
(ii) Maintaining self-tolerance
What allows Tregs to respond to very low concentrations of IL-2?
IL-2 receptor alpha chain (CD25) is highly expressed in Tregs
What gene does FoxP3 in Tregs repress, and what is the result of this?
IL-2 gene
As a result, Tregs scarcely produce any IL-2 and are highly dependent on exogenous IL-2 for their survival
Activated Tregs repress the activity of?
activated CD4+ T cells
FoxP3 is a master regulator of?
Treg development and function
What are important for induction of FoxP3?
TCR and CD28 costimulatory signals, as well as IL-2 and an autocrine FoxP3-dependent feedback loop
How is FoxP3 expression regulated?
By several transcription factors: NFAT, AP-1, STAT5, CREB binding to the promoter region of the FoxP3 gene
As well as 3 highly conserved non-coding sequences (CNS1-3) in the genomic FoxP3 region
Tregs account for __% of T cells
~5-15%
What produces the majority of FoxP3+ Tregs in the immune system?
the thymus
(generated as a separate lineage at the stage of CD4+ SP thymocytes)
Some T cells differentiate into Tregs in…
the periphery, especially in the intestinal mucosa
pTregs develop from conventional CD4+ in the periphery after antigen encounter or…
due to the influence of IL-2 and TGFβ
FoxP3 Tregs constitutively express __ and __ on the cell surface at high levels.
CD25 (high affinity IL-2 receptor) and CTLA-4
How do Tregs inhibit the immune system?
- Secretion of inhibitory cytokines (IL-10, TGFβ, IL-35) and intracellular molecules (Granzyme, cAMP, IDO)
- Cell-contact inhibition mechanisms involving specific cell surface receptors: CTLA-4, CD25, CD39
- Peripheral tolerance (inhibition of any self-reactive CD4 or CD8 cells that might have escaped thymic education)
High levels of Tregs in cancer patients are often associated with?
poor prognosis because they create an immunosuppressive environment
Name the 3 main groups of memory T cells
- Effector memory T cells (Tem)
- Central memory T cells (Tcm)
- Tissue-resident memory T cells (Trm)
Role of effector memory T cells
- recirculate between blood and non-lymphoid tissues
- provide a rapid response to reinfection
- carry out cytotoxic functions and secrete effector cytokines upon antigen reencounter
Effector memory T cell markers?
CD62Llo/CCR7lo
however, they express integrins and chemokine receptors required for localisation in inflamed/infected tissues
Role of central memory T cells
recirculate via secondary lymphoid organs (increase with time after infection)
Central memory T cell markers?
CD62Lhi/CCR7hi
(CD62L is an L-selectin involved in adhesion, CCR7 homes the cells to the T cell zones in SLOs)
Role of tissue-resident memory T cells
- Provide enhanced localised immunosurveillance and protect the peripheral tissues such as skin, lungs, brain, liver, bladder, GIT
- Rapidly activated to fight infection
What is different about tissue-resident memory T cells?
They do not circulate
Which two molecules form a heterodimer receptor for E-cadherin?
CD103 and integrin β7
What allows Trm cells to adhere to tissue for a long time?
Integrin CD103 (αE-type integrin), LFA-1 & VLA-1
Which cell surface markers promote tissue retention?
CD69 and CXCR3
CXCR3 binds?
CXCL9 and CXCL10, produced by inflamed tissue
Where do CD4 and CD8 Trm cells mainly settle?
in the basement membrane of mucosal tissue and in the lymph nodes
What are CD8+ Trm cells important for?
detecting tumour development, can also kill virus-infected cells
