T cell activation and generation of effector T cells Flashcards
Describe how T cell circulate before activation
Naïve T cells, those which have not yet encountered their specific antigen, primarily circulate between the secondary lymphoid organs and the blood. These secondary lymphoid organs include the lymph nodes, spleen, and Peyer’s patches. T cells constantly scan these areas for the presence of their specific antigen.
The circulation process involves a series of carefully regulated steps:
1) Entry into Lymph Nodes: T cells enter lymph nodes from the blood via high endothelial venules (HEVs), using a process known as extravasation. This process is guided by specific molecules including selectins, integrins, and chemokines, which facilitate the rolling, activation and tight adhesion of T cells to the endothelium of the HEVs, and their subsequent diapedesis into the lymph node parenchyma
2) Scanning Antigen-Presenting Cells (APCs): Once inside the lymph node, T cells move through the T cell zones, making transient contacts with dendritic cells, the primary APCs, to check for the presence of their cognate antigen
3) Exit from Lymph Nodes: If no specific antigen is found, the T cells exit the lymph node via the efferent lymphatics, return to the blood, and continue to another lymph node.
Describe how T cell circulate after activation
When a T cell encounters its specific antigen on an APC in a lymph node, it becomes activated; undergoes clonal expansion and differentiation, producing a large number of effector T cells and memory T cells.
1) Effector T cells: following activation, the homing receptors on T cells downregulate and upregulate the receptors that guide them to the site of infection or inflammation (integrins for adhering to the endothelium of blood vessels in inflamed tissues). Effector T cells also express receptors that allow them to leave the lymphoid organs and blood vessels and enter the tissues via extravasation (The inflammation-induced expression of adhesion molecules and chemokines in the vascular endothelium of the affected tissue aids this extravasation process), particularly inflamed tissues where their cognate antigen are likely to be found. In the tissues, they perform their effector functions, such as killing infected cells (cytotoxic T cells) or assisting other immune cells (helper T cells)
2) Memory T cells: Some of the activated T cells develop into memory T cells. These cells can persist long after the antigen has been cleared, providing a rapid and strong response upon re-exposure to the same antigen. Memory T cells circulate through the blood and lymphoid organs like naïve T cells but also enter non-lymphoid tissues to enhance surveillance
Identify the main APC involved in T cell activation
1) Dendritic Cells (DCs):
- Most potent APCs and crucial for initiating a T cell response, especially for naïve T cells
- DC capture antigens in the tissues and then migrates to the lymph nodes where they present these antigens to T cells
- Present antigens on both MHC class II and I molecules thus activating both CD4+ helper T cells and CD8+ cytotoxic T cells respectively
2) Macrophages:
- Mainly presents antigens to effector T cells
- After phagocytosing pathogens, they process and present antigens to T cells in the tissues where the infection is occurring.
- primarily leads to the activation of CD4+ helper T cells
3) B cells:
- Can present antigen to helper T cells, which is essential for their own activation and differentiation into antibody-producing plasma cells.
- B cells capture antigens through their B cell receptor (BCR), allowing them to present antigens that they specifically recognise
4) Myeloid cells:
- Able to detect the presence of infection
- Once activated, phagocytose processes and present foreign antigens in the context of MHC class I and II molecules. And present those to T cells
explain why the presentation of antigen – MHC complexes is not enough to activate a T cell
T cell activation requires more than TCR engaging with the antigen-MHC complex, the process also requires additional signals, referred to as co-stimulation.
This dual requirement ensures that T cells are activated only in the appropriate immune context; reducing the risk of inappropriate or excessive immune response that could damage the host.
There are two key reasons for this:
1) Activation Threshold:
- To avoid accidental activation, T cells have a relatively high threshold for activation
- T cell needs to encounter an APC displaying many copies of the relevant antigen-MHC complex, along with appropriate co-stimulatory signals
2) Anergy and Tolerance:
- Co-stimulation maintains immune tolerance
- If a T cell receives only the antigen-MHC signal without co-stimulation, the T cell can become anergic, meaning it is unresponsive to further antigen stimulation
Co-stimulation typically involves interactions between T cell’s CD28 molecule and the B7 family of molecules (CD80 and CD86) on the APC. As well as TNF receptors with TNF molecules
After the initial activation, T cells also require cytokines for their survival, proliferation and differentiation, these cytokines act as a third signal in the activation process and influence the differentiation of T cells into various effector subsets
Identify the main cell surface receptors involved in positive or negative co-stimulation
Positive Co-Stimulation:
- CD28: interacts with the B7 family molecules (CD80 and CD86) on APC. Providing the second signal for T cell activation for T cell proliferation, survival and cytokine production
- ICOS (Inducible T-cell COStimulator): another co-stimulatory molecule, which is induced upon T cell activation, it interacts with ICOS ligand (ICOSL) on APCs to enhance T cell survival and cytokine production
- CD40L (CD154): CD40L on T cells interacts with CD40 on APCs, important for the activation of B cells by T cells
Negative Co-Stimulation
- CTLA-4 (Cytotoxic T-Lymphocyte-Associated protein 4): An inhibitory receptor expressed on T cells. It binds to B7 molecules with high affinity than CD28. Acting as a brake to control excessive T-cell response
- PD-1 (Programmed cell death protein 1): Inhibitory receptor that is upregulated on T cells following activation. It binds to PD-L1 and PD-L2 on APCs and tissues, inhibiting T-cell activation and promoting tolerance to self-antigens
- LAG-3 (Lymphocyte-activation gene 3), TIM-3 (T-cell immunoglobulin and mucin domain containing-3) and TIGIT (T-cell immunoreceptor with Ig and ITIM domains): inhibitory receptor on T cells
Describe the outcomes of successful co-stimulation or lack thereof
Successful Co-stimulation:
- T-cell proliferation: promotion of division and proliferation of T-cells, expanding the population of T cells specific for the presented antigen, enhancing immune response
- Cytokine production: Stimulation of T cells to produce cytokines, mediate communication between immune cells and regulate immune response
- T cell survival: Promoting the expression of survival genes and inhibiting apoptosis
- T cell differentiation: T cells into various effector cells like helper T cells (Th1, Th2, Th17) or cytotoxic T cells (CTLs)
Lack of Co-stimulation
- Anergy: Unresponsiveness or tolerance in which T cell does not respond to antigen stimulation = anergic
- Apoptosis: Helps to maintain immune tolerance and preventing autoimmunity by eliminating self-reactive T-cells that have been activated by self-antigens
- Regulatory T cell induction: Tregs differentiation when TCR signalling without co-stimulation. Tregs help to control immune response and maintain self-tolerance by suppressing the activation and function of other immune cells
Explain the difference between the roles of polarising cytokines vs effector cytokines
Polarising cytokines:
- Influences the differentiation of naïve T cells into different types of effector T cells. Specific to pathogens thus critical determinant of the nature of the immune response
- For example, in the presence of IL-12 and Interferon-gamma (IFN-γ), naïve CD4+ T cells can differentiate into Th1 cells, which are effective against intracellular pathogens.
- In the presence of IL-4, naïve cells can become Th2 cells, geared towards extracellular parasites and mediating allergic responses
Effector Cytokines:
- Effector T cells under the influence of polarising cytokines, begin to produce their own cytokines, known as effector cytokines, which enables T cells to carry out their specialised function
- Th1 cells produce IFN-γ, which activates macrophages, enhancing their ability to kill intracellular pathogens
- Th2 cells produce cytokines like IL-4, IL-5 and IL-13, which promote antibody production by B cells, eosinophil activation, and mucosal responses = parasitic infection or allergic response
Name and identify the role of key cytokines for control of T-cell activation
- IL-2: Acts as an autocrine growth factor, promoting T cell proliferation and clonal expansion. Produced and upregulated when TCR-MHC with co-stimulation.
- IL-12: Produced by APCs (DC and macrophages), aids in the differentiation of naïve T cells into Th1
- IL-4: Drives differentiation of naïve T cells into Th2 cells. Also promote B cell class switching to produce IgE antibodies
- IL-6: Aid in the differentiation of T cells into Th17 cells, defence against extracellular bacteria and fungi. Inflammatory contribution
- TGF-β (Transforming Growth Factor-beta): Suppressive effect on T cell activation. It can inhibit T cell proliferation and can aid in Tregs differentiation to modulate immune responses and maintain tolerance to self-antigens
- Interferon-gamma (IFN-γ): Produced by Th1 cells, promotes cellular immune responses by activating macrophages and enhancing the expression of MHC molecules on APCs = increased antigen presentation
- IL-10: Anti-inflammatory cytokine, inhibits cytokine production by Th1 and reduces the expression of MHC II. and co-stimulatory molecules on APCs ∴ ↓T cell activation
Explain the concept of effector function of T cells
1) CD8+ Cytotoxic T cells (CTL):
- Kills cells that are infected with viruses or other intracellular pathogens.
- By recognising pathogen-derived peptides presented on the surface of infected cells by MHC.
- Upon recognition, they release perforin and granzymes that induce apoptosis.
- They also express Fas ligands which bind to Fas on target cells to trigger apoptosis
2) CD4+ Helper T cells (Th cells): Recognise MHC II and differentiate:
- Th1 cells: produce IFN-γ, which helps activate macrophages to kill ingested microbes and promotes cell-mediated immune responses
- Th2 cells produce IL-4, IL-5, and IL-13, which support humoral immune responses by helping B cells to produce antibodies. IL-4 is vital for the class switching of B cells to produce IgE (vs parasites and allergens). IL-5 promotes the activation and survival of eosinophils (vs parasites and allergens)
- Th17 cells produce IL-17 and IL-22; promote inflammatory responses against extracellular bacteria and fungi by inducing the production of other pro-inflammatory cytokines and chemokines, thereby leading to the recruitment of neutrophils
- T follicular helper (Tfh) cells produce IL-21 and provide help to B cells in the germinal centres of lymph nodes for their proliferation, somatic hypermutation, class-switch recombination, and differentiation into plasma cells and memory B cells
- Th9 and Th22 cells: Produces IL-9 (Asthma and allergic responses) and IL-22 (Skin inflammation and healing)
3) Regulatory T cells (Tregs):
- maintain immune tolerance and prevent autoimmunity by suppressing the activation and proliferation of self-reactive T cells
- main effector molecules are inhibitory cytokines such as TGF-β and IL-10
Explain how Th-1 AND Th-2 cells differentiate and carry out their effector functions
Th1 Cell Differentiation and Effector Functions:
- Th1 cell differentiation is primarily driven by IL-12 and IFN-γ.
- IL-12 produced by activated macrophages and DC
- IFN-γ produced by NK cells or initial T cell activation
- IL-12 binding triggers expression of T-bet, a transcription factor that promotes Th1 lineage
- T-bet expression further stimulates IFN-γ production; positive feedback loop (crucial in defending vs intracellular pathogens)
- Primarily, Th1 cells facilitate cell-mediated immunity via the release of cytokines such as IFN-γ ∴↑macrophage function
- Th1 cells also produce IL-2 for the proliferation of cytotoxic T cells and lymphotoxin to kill infected cells
Th2 Cell Differentiation and Effector Functions:
- IL-4 stimulates the expression of GATA3 (transcription factor), promoting the Th2 lineage
- Th2 produces IL-4, IL-5 and IL-13
- Il-4: promotes B cell class-switching to IgE, crucial for mast cell activation and allergic responses
- IL- 5: Activation and recruitment of eosinophils
- IL-13: induces mucus production, defence vs. parasites/allergic reactions
Cross-inhibition ensures immune response is tailored, IFN-γ produced by Th1 cells inhibits Th2 differentiation, and IL-4 from Th2 cells inhibits Th1 differentiation
