Cell-mediated immunity Flashcards
what happens to T cells in the thymus?
antigen-independent rearrangement of TCR genes
- after thymic selection, “naïve” T cells expressing T cell receptor and CD4/CD8 are generated.
- Selection process is stringent – only 5% of T cells will leave the thymus
what happens to T cells in secondary lymphoid tissue?
antigen-dependent T cell activation:
- T cells activated by antigen-presenting cells displaying MHCI/MHCII + peptide differentiate into “effector” T helper or T cytotoxic cells.
- Generate cytokines or directly kill infected host cells.
Effector T cells are what contribute to cell-mediated immunity
what signals are involved in the production of effector T cells:
signal 1: Naïve T cell will enter lymphoid tissue and recognition of MHC + peptide + co-receptor (CD4/8)
- T cell recognises antigen and becomes activated
signal 2: Recognition of co-stimulatory molecule(s)
- CD28 and B7 are both members of human immunoglobulin gene superfamily
- T cells exposed to signal 1 in the absence of signal 2 become unresponsive/tolerised
signal 3: Cytokines convert activated T cells into different subsets = signal 3
- T cells will develop into a certain subset relevant to the infection type
what co-stimulatory molecule is important in activation of T cells?
One of the best characterised is B7 expressed by dendritic cells, macrophages, B cells (APCs)
how does B7 act to stimulate T cells?
- B7 on APC interacts with CD28 on surface of T cell, inducing expression of IL-2 and IL-2 receptor by the T cell – auto-stimulatory
-IL-2 acts in autocrine fashion on CD4+ve T helper cells; also required for CD8+ve cytotoxic T cell activation - Other cytokines direct T cell differentiation into different subsets of CD4+ve T effector cells (Signal 3)
how are CD4+ve T cells organised into subsets?
they differ in the cytokines that they produce
- Different cytokines induce activated “naïve” T helper cells (a.k.a. TH0 cells) to differentiate into various T cell effector subsets.
what triggers TH0 cells to differentiate into T cell subsets?
TH0 is the naïve T cell which receives signal 3 cytokines to differentiate into a subset of T helper cell
- Signal 3: cytokines made by antigen-presenting cell vary depending on type of infection
what are the different T cell subsets?
TH1, TH2, TH17, TFH, TREG
what distinguishes T cell subsets from one another? why is this important?
The T cell subsets differ in the types of cytokines they make and their role in immune responses
- Helps ensure pathogen appropriate immunity – fine tunes the immune response
what triggers transition of TH0 to TH1?
cytokines IL-12 and IFN-gamma
what is the role of TH1 cells?
- produce IL-2 (autocrine), IFN-gamma and TNF
- Most abundant T helper subset in blood
- Activate macrophages to induce inflammation (classic cell-mediated immunity)
- Important in intracellular infections and indirectly in extracellular infections via IgG
- Induce B cells to make IgG1 and IgG3 opsonising antibodies and can activate complement
- Important for development of cytotoxic T cells = IL-2
what triggers transition from TH0 to TH2?
cytokine IL-4
what is the role of TH2 cells?
- produce IL-4, IL-5 and IL-13
- Activate eosinophils and mast cells
- Important in helminth infections and allergy
- IL-4 and IL-13 induce B cells to make IgE – promote mast cell degranulation and inflammation
what triggers transition from TH0 to TH17?
cytokines TGF-beta and IL-6
what is the role TH17 cells?
- Produce IL-17 and IL-22
- Activates epithelial cells, fibroblasts, found near mucosal surfaces
- Act at mucosal surfaces to promote inflammation = recruit neutrophils
- Important in fungal and extracellular bacterial infections
- Role in autoimmune disease e.g. Crohn’s disease
- Recruit neutrophils to sites of infection
what triggers transition from TH0 to TFH?
cytokine IL-6
what are lymphoid follicles?
- Lymph nodes are divided into areas predominantly T cells and follicles where B cells differentiate into plasma cells
- Follicular T cells reside in these follicles
what is the role of T follicular helper cells?
- Produce IL-21
- Found in lymphoid follicles
- Help naïve B cells differentiate into plasma cells and memory cells
- Promote somatic hypermutation and class switching
- Cytokines switch on AID enzyme
what does TFH function require?
Contact-dependent – TFH requires interaction between co-stimulatory molecules CD154 and CD40 to enable B cell and T cell to touch
- This occurs in the follicles of the lymph nodes
what determines the immunoglobulin class that TFH cells induce B cells to make?
Depending on type of infection, different cytokines are produced by TFH cells:
- Causes activation of appropriate innate responses to help body deal with infection
- B cells promoted to differentiate into cells which make IgG, IgE, IgA
what causes the transition from TH0 to Treg?
cytokine TGF-beta
what is the role of Treg cells?
- Heterogeneous group which suppresses immune responses
- Induced Tregs suppress T cell subsets
what are the features and roles of natural Treg cells?
- develop in thymus
- recognise MHC+self-peptide
- suppress via contact, IL-10 and TGF-beta
- target dendritic cells, effector T cells
- suppress autoreactive T cells
what are the features and roles of induced Treg cells?
- develop in periphery mucosal lymphoid tissue
- recognise MHC + non-self peptide
- suppress via IL-10 and TGF-beta
- target effector T cells
- causes downregulation of mucosal immunity, inflammatory responses
how do cytotoxic T cells induce target cells to undergo apoptosis?
- Proteases (granzymes) from cytotoxic T cell enter target cell via perforin channel and trigger caspase cascade
- fas ligand on surface of cytotoxic T cell induces clustering of fas (“death receptor”) on target cell and triggers caspase cascade to induce apoptosis
- Fas pathway may be important in downregulating immune responses
- Fas is normally distributed evenly on target cell, and when interacting with cytotoxic T cell it clusters
is killing by cytotoxic T cells effective?
Yes:
- SPECIFIC - only infected cells bearing antigen are killed
- EFFICIENT - granzymes are pre-formed; a single cytotoxic T cell can kill 100s of infected targets
- “CLEAN” – enzymes formed during apoptosis degrade viral DNA and destroy non-viral pathogens. Apoptotic cells are taken up by phagocytes
what cytokines can cytotoxic T cells produce?
IFN-gamma
TNF-alpha
what causes allergy and autoimmune disease?
inappropriate activation of T cell subsets
what is allergy? how is it caused?
- Disease following an immune response to innocuous antigen (ALLERGEN).
- Mostly IgE-mediated a.k.a. Type I Hypersensitivity
what are the different hypotheses on why allergy is increasing in developed countries?
The hygiene hypothesis
Counter regulation/’old friends’ hypothesis
what is the hygiene hypothesis of allergy?
- Children brought up on farms, or from large families, are less prone to develop allergy.
- Early, repeated childhood infections may be protective.
- Insufficient exposure to certain types of infection (“dirt”) skews TH1/TH2 balance towards TH2?
- BUT there is a negative correlation between helminth infections and allergic disease.
what is the counter regulation/old friends hypothesis of allergy?
- Childhood infection protects against allergy by promoting IL-10 production: (Treg ↑, TH1 ↓ and TH2↓)
- Infection with microbes or larger parasites plays a critical role in driving immunoregulation e.g. promotes formation of Treg, IL-10
- Human immune system and “Old friends” co-evolved
- May also explain rise in autoimmune disease in the west (TH1/TH17-driven)
- Infections are needed to promote Tregs to dampen down the immune response
what are gamma-delta T cells?
- 5% of T cells express gamma-delta chains with no CD4/CD8
- Generated earlier in development than αβ T cells – these are the T cells that we make first
- Often found at mucosal epithelium lining mucous surfaces
- Less diverse, recognise a broader range of antigens (including lipids, phosphorylated antigens, DAMPs e.g. heat shock proteins)
- Do not appear to require processing or presentation by MHCI/II – independent of antigen presentation
what is the role of gamma-delta T cells?
- Can make cytokines e.g. proinflammatory IL-17, IFN-γ, TNF but also cytotoxic.
- Can act as antigen presenting cells to αβ T cells.
- Role in various intracellular bacterial, viral and parasitic infections (mycobacteria, flu, HIV, malaria) and also in cancer (not MHC restricted)
- May “bridge” innate and adaptive immunity
why are immune responses terminated?
Once an infection is cleared, 99% of activated and effector cells die
- Wasteful to keep immune response turned on
- Left with memory cells to prep immune system under reinfection
how is the immune response downregulated?
by Tregs and cytotoxic T cells
inhibitory immune checkpoints
what are inhibitory immune checkpoints?
Inhibitory immune checkpoints expressed on lymphocytes – when they bind a ligand, it causes inactivation of the lymphocyte
what is an example of an inhibitory immune checkpoint?
e.g. CTLA-4 (induced on activated T cells) binds with high avidity to B7.
- Engagement of CD28 on naïve T cells with B7 provides the co-stimulatory signal for activation of naïve T cell
- Once T cell has been activated, CTLA-4 engagement with B7 inhibits T cell activation and switch it off (higher avidity than CD28-B7
give an example of how inhibitory immune checkpoints are involved in terminating the immune response:
lymphocyte receptors with immunoreceptor tyrosine inhibitory motifs (ITIM) – when phosphorylated, these inhibit lymphocytes
- FcγRIIb found on B lymphocytes – when it binds IgG it switches the B cell off
- PD-1 on activated B and T lymphocytes – interacts with PD-ligand, which is widely expressed
- PD = programmed death (downregulation and apoptosis of B cell)
how do cancer cells subvert immune checkpoints?
- Cancer cells express PD-ligand which switches off the lymphocytes
- Agents that target immune checkpoints may be used in cancer immunotherapy.
