T cell subsets and functions Flashcards
What are the different types of T cells?
Explain their main function
List the pathogens they target
How do CD8+ T cells cause lysis of target cells
- Release cytotoxic granules at site of contact with target cell (must be directed in order to avoid damaging innocent bystander cells)
OR - Engage Fas/FasL interaction
Describe how CD8+ T cells cause lysis of target cells
CTLs and NK cells use a variety of different mechanisms to kill their targets. These include:
* direct cell–cell signaling via TNF family molecules;
* pore formation, which allows apoptosis-inducing proteins to access the target cell cytoplasm;
* indirect signaling via cytokines.
All of these mechanisms culminate in target cell death by apoptosis.
Describe how Cytotoxicity may be signaled via TNF receptor family molecules on the target cell
CTLs can initiate apoptosis in their targets via the extrinsic pathway using members of the TNF receptor group of molecules. These include:
* Fas (CD95);
* TNF receptors.
CD4 and CD8 T-cells can initiate cell death via expression of Fas ligand, a member of the TNF family. Fas ligand recognizes the cell surface protein Fas. Cross-linking leads to trimerization of Fas and recruitment of FADD to the death domain in the cytoplasmic tail of Fas. FADD recruits caspase 8 or 10, leading to apoptosis.
2) TNFa is produced by CTLs . TNFR1, one of the receptors for TNFa, recruits caspases 8 and 10 via TRADD. The ability to induce cell death is dependent on the presence of the death domain in the cytoplasmic tail. TNF receptor family members that lack the death domain do not mediate caspase-dependent cell death. Apoptotic signals delivered by members of the TNF family are Ca2+ independent
Describe how CTL cell can use granules containing perforin and granzymes to trigger apoptosis
Activated CTLs contain lytic granules. Upon recognition of a target cell, these granules polarize to the site of contact, the immunological synapse, releasing their contents into a small cleft between the two cells.
The lytic granules contain the pore-forming protein perforin, and granzymes.
Perforin is inactive when located within the granules, but undergoes a conformational activation, which is Ca2+ dependent. perforin is able to form homopolymers,
inserting into the membrane to form a circular pore of
approximately 16 nm diameter. Unlike C9, perforin is able
to bind membrane phospholipids directly in the presence of Ca2+
Once perforin has formed a pore in the cell membrane, granzymes may enter the target cell cytoplasm and cleave a number of substrates, leading to apoptosis via the intrinsic pathway:
Describe the actions of perforin
Perforin is a monomeric pore-forming protein that is related both structurally and functionally to the complement component C9.
Perforin is inactive when located within the granules, but undergoes a conformational activation, which is Ca2+ dependent.
Like C9, perforin is able to form homopolymers,
inserting into the membrane to form a circular pore. Unlike C9, perforin is able to bind membrane phospholipids directly in the presence of Ca2+.
Describe the actions of granzyme from CTLs
Once perforin has formed a pore in the cell membrane, granzymes may enter the target cell cytoplasm and cleave a number
of substrates, leading to apoptosis via the intrinsic
pathway:
* granzyme B cleaves pro-caspases 3, 7, and 8, triggering apoptosis in the target cell.
* Granzyme B-deficient mice show delayed but not ablated cytotoxicity, illustratingthe importance of other pathways;
* granzyme A triggers apoptosis via a caspase-independent pathway. It targets the ER-associated protein complex SET, activating DNAse, which nicks the target cell DNA. It also cleaves nuclear laminins, leading to loss of nuclear structure, and acts in the mitochondria to increase ROI production.
What are the roles of CD4+ T cells?
- Activate and ‘help’ other cell types to co-
ordinate immune response - Achieved through expression of cell surface
proteins and soluble cytokines - Acquired Immune Deficiency syndrome (AIDS)
results from loss of Helper T cells following HIV infection
List all the T-helper cells and the cytokines they release
What are the factors that influenc the differentiation fates of Th cells?
- the sites of antigen presentation;
- co-stimulatory molecules involved in cognate cellular interactions;
- peptide density and binding affinity – high MHC class II peptide density favors TH1 or TH17, low densities favor TH2;
- APCs and the cytokines they produce;
- the cytokine profile and balance of cytokines evoked by the antigen;
- receptors expressed on the T cell;
- activity of co-stimulatory molecules and hormones present in the local environment;
- host genetic background.
List the cytokines which influence the differentiation of Naive CD4+ T-cells
Th1 cells activate macrophages to kill bacteria
within them
Describe this
- Some infections e.g. mycobacteria hide in
phagosomes – protects them from MHC-I
antigen presentation - But peptides from these bacteria will be
presented by MHC-II as macrophages are
professional antigen presenting cells - Recognition of peptide/MHC-II on an
infected macrophage causes Th1 cell to
produce IFNg - IFNg activates the macrophage
- Following activation, macrophage will fuse phagosome (which contains the bacteria) with
lysosomes. Reactive oxygen and nitrogen species then kill bacteria
Why not have macrophages activated all the time?
- Requires too much energy
- Results in localised tissue destruction due to release of reactive species
Activation of CD8+ cells can be CD4+-
dependent.
Describe this
- Recruited CD4+ cells can induce the secretion of secreted chemokines from the DC, leading to the attraction of CD8+ cells
- NKT cells can also be involved in this process
The differentiation of these cells may
be affected by the CD4+ cell cytokine profile, with CTLs commonly associated with TH1 responses and less commonly found when TH2 cells are present. Thus:
* IFNg and IL-12 may encourage CTL1 generation;
* IL-4 may encourage CTL2 generation.
However, both CTL1 and CTL2 cells can be cytotoxic and kill mainly by a Ca2+/perforin-dependent mechanism
Th1 cells provide help for B cells for antibody
production
- B cells process and present antigens that bind to their surface immunoglobulin
- Binding of antigen by surface Ig leads to receptor mediated endocytosis
- Antigen delivered to MHC class II for presentation
- Will therefore stimulate helper T cells that recognise the same antigen as the B cells
- IFNg production stimulates B cells to up-regulate antibody production
- This is predominantly IgG2a
IL-2 promotes B cell division. IFNg promotes affinity maturation and class switching to IgG2a, which acts as an opsonin and fixes complement.
T cell follicular helper cells (Tfh cells) also
cells provide help for B cells
Describe this
*The T follicular helper (TFH) cells express the chemokine receptors CXCR5 that enables them to migrate towards the B cell follicles.
*named for their localization in germinal centres
*It also produces cytokines such as IL-4 and IL-21 (a cytokine that is critical for germinal center
formation) that support B cell proliferation and differentiation into antibody-secreting cells and it has the costimulatory receptor ICOS that enhances interactions with ICOSL+ B cells.
*Upregulation of CXCR5 allows chemotaxis towards CXCL13 produced in B cell zone
*Stimulate Ig class switching and somatic mutation
*Also promotes B cell memory expansion
Describe the interaction of B cells and CD4+ T cells
The survival of germinal centre (GC) B cells also depends on repeated interactions between CD40 on B cells and its ligand CD154 on T cells
Describe the function of Th2 cells
- Th2 cells help to control parasitic infections by
promoting IgE production and by promoting the function of eosinophils and mast cells - Produce IL-4, IL-5 and IL-13
Eosinophils and mast cells are needed to
clear parasitic infections
- Most helminth parasites are too large to be phagocytized, and the IgE system is believed to have evolved to deal with larger invaders
- IgE is the link that connects eosinophils to the outer surface of a parasitic worm
- IgE-bound pathogens bind to high affinity FceRI and FceRII receptors found on the surface of eosinophils and mast cells (and basophils)
- The large cytoplasmic granules of eosinophils contain a variety of proteases and toxic proteins that, in aggregate, can often kill larval intestinal parasites to which the eosinophils are attached
- Mast cells (activated by IL-5 and coated by IgE) degranulate and release histamine, serotonin and leukotriene at the site of infection.
*These can cause contractions of the smooth muscle cells of the intestinal walls as a physical mechanism for expelling the worms from the
digestive tract.
Describe Ig gene class switching leading to IgE transcription
- IL-4 activates STAT6
- STAT6 expression promotes Ig class switching to
IgE and IgG1
Th1/Th2 balance can determine the outcome of infection - leprosy
Describe this
- Infection with Mycobacterium leprae
- Th1 cells predominate – tuberculoid leprosy, bacterial growth controlled, minor damage
- Th2 cells predominate – lepromatous leprosy, bacteria grow abundantly, gross tissue damage
Describe Th17 cells
- Most recently discovered subset, secrete IL-17
- Help protect against extracellular bacteria and fungi by stimulating neutrophils
- Over-represented in autoimmune diseases
TH17 cell cytokines include IL-17A, IL-17F, TNFa, and IL-22.
*the effects of TH17 cells can promote inflammation - important for the recruitment of neutrophils and induction of antimicrobial peptides from resident cells
What happens to immune cells once the infection is cleared?
Resolution of infection and memory
When infection is cleared the majority of effector B and T cells die by “neglect” and enter apoptosis
* Some remain as memory cells. Memory T cells generally express high levels of Bcl-2, which may contribute to the rescue of memory populations
* Both CD8+ and CD4+ populations establish
memory
* Individual memory T cells are relatively short-lived; therefore need to divide fairly frequently
* Memory T cells are maintained by IL-7 and IL-15 with stimulation from self antigens
* memory B cells, plasma cells do not express
surface BCR or MHC class II.
CD8+ T cell memory is longer-lived than CD4+ memory
Describe this
CD4+ T‐ cells are inherently less proliferative
than B cells and CD8+ T-cells, and the CD4+
memory T‐ cell population appears to decline
following antigen clearance, while the CD8+
memory T‐ cell population, if established, is
typically stable
Describe the different types of memory T cells
*Central memory; circulate between the blood and SLO
*Tissue-resident, mainly CD8+ cells. Often quite-long-lived
*Stem cells. Two populations: commonly short-lived (divide every few months; half-life = 7 months. Rarer, long-lived ; half-life = 9 years)
*Effector memory; migrate from the blood into non‐ lymphoid tissues
