T-cells Flashcards
T-cells
- Thymus derived
- Make up 60-80% of lymphocytes (largest population)
Where are T-cells found?
- Paracortex of lymph nodes
- Blood
- Peyer’s patches
- Spleen
T-cell receptor
Express T-cell receptor (TCR) on their surface to recognize specific antigens
Different classes of T-cells
Based on different subunits used to make them
- Alpha beta-T cells (conventional)
- Gamma delta T cells (non-conventional)
Difference between non-conventional T-cells
They do not need to be presented antigen by antigen-presenting cells via the MHC
Alpha beta T cell classification
Based on CD molecule expression
- CD4+ (T-helpers)
- CD8+ (cytotoxic)
CD4+ T helper lymphocytes
- Provide help (directors of immune response)
- Recognizes antigen presented via MHC II (on phagocytic cells)
- Release cytokines
- Influence cell-mediated and humoral immunity
CD8+ cytotoxic lymphocytes
- They kill other cells
- Recognize antigens presented via MHC I (on all cells)
- Releases perforins and granzymes
T cell development
- Lymphoid progenitors migrate from the bone marrow to the thymus
- Progenitors develop their specific T cell markers
- T cells undergo positive and negative selection in the medulla and cortex as the cells migrate by thymus epithelial cells (TEC) and antigen-presenting cells
- Functional T cells that pass will migrate to the lymphoid tissues and are now called naïve T cells (not encountered their antigen yet but have a specific receptor on their surface)
Why do T cells go through a selection process?
To ensure that selected cells can recognize our own MHC but do not recognize self-peptides that are presented by the MHC molecule. This ensures that our T cells will not kill our own body cells
Positive selection
Positively selecting T cells that can recognize MHC molecules. Cells that do not recognize MHC are of no use and are being deleted
Negative selection
Select cells that do not recognize our self-peptides
How does selection process work?
Self-reactive T cells are binding strongly (high affinity). T cells that have high affinity to self-MHC peptide complexes are eliminated
- Binding affinity is a major determinant in T cell selection. High affinity would mean there are auto reactive and low affinity would mean decreased specificity
Percentage that actually are selected for in the thymus (mouse example)
2-4%
Mature T cells recognize antigen twice
- First time- when T cells are activated in the lymphoid tissues. They are naïve T cells and are being presented antigen by antigen presenting cells
- Leads to activation of T cells and creation of clones (effector T cells). T cells will leave lymphoid tissues and migrate to site of infection
- Second time- when effector T cells encounter their antigen outside of the lymphoid tissues. They are seeing it on the MHC presented by tissue cells and in response they kill the cells and or secrete cytokines
Signals involved in first time T cell antigen recognition
- Signal 1- antigen-specific interaction: antigen being presented to them by antigen-presenting cell via MHC
- Signal 2- co-stimulatory molecules: information about type of immune response needed
- Signal 3- instructive cytokines: signal to “do it now”
What is antigen-presenting cell able to provide naïve cell?
APC phagocytosed foreign material and at the same time is recognizing a danger signal with a pattern recognition receptor. So it knows type of danger and can tell T cell the type of response needed and when to do it
Stabilization of MHC and T cell interactions
T-cell receptors (TCR) and MHC are stabilized by the CD4 or CD8 molecules but they are not involved in recognition of the antigen
MHC’s as general presenters
- They can present multiple antigens. Therefore one APC can interact with many different T-cells
Ex. Humans express 6 different haplotypes of MHC I on their cell surface and these can present a bunch of different peptides. Variation depends on what we get from our parents. These different MHCs present all antigens that are present (both foreign and self)
TCRs as specific receptors
- TCR is very specific for each individual antigen. One T cell only recognizes one antigen
- Specificity occurs through gene re-arrangement
o Somatic recombination
o Transcription splicing
o Translation
What happens if T cell does not receive signal 2 and signal 3?
If antigen presenting cell has not recognized danger signal then no T-cell activation and signal 2 and 3 will not be provided
- Means no co-stimulatory molecule and no cytokines to drive T cell differentiation
Signal 2
- Co-stimulatory molecules
- Important to drive the immune response towards specific types to fight intracellular or extracellular pathogens
Signal 3
- Cytokines
- Provide the do it now signal
Does the T cell need signals 2 and 3 during the second time activation?
No
What has the antigen presenting cells provided to a T cell to get a CD8+ T cells (cytotoxic T lymphocyte)?
Signal 1: antigen presented from MHC
Signal 2: co-stimulatory molecule (CD80/86 on APC and CD28 on CD8 T cell)
Signal 3 cytokines (IL-12, IFN-gamma, IFN alpha, IFN beta)
CD8+ cytotoxic T lymphocytes
- Recognize peptide sequences bound to MHC I molecules (on all nucleated cells)
- A major contributor to the T helper 1 (Th1) response
- Main function to kill infected cells
Main pathways for cell destruction by CD8+ cytotoxic T-lymphocytes
- Perforin/granzyme pathway
- CD95 (Fas-FasL) pathway
Perforin/granzyme pathway
- Cytotoxic T-lymphocyte (CTL) recognition of MHC I and peptide (no signal 2 or 3 needed)
- Perforin is secreted from CTL and forms pores in the infected cell membrane
- Granzymes enter through pores or by endocytosis. Stimulate cytochrome C release from mitochondria which activates a caspase cascade inducing apoptosis
Fas/FasL pathway
- Activated CD8+ CTLs and NK cells express FasL (CD95L)
- Infected cells express Fas
- The binding of the two will induce apoptosis in the infected cells
Apoptosis
- Signal transduction results in caspase activation
- Cell begins to round, chromatin condenses
- Loss of nuclear membrane, chromatin released into cytoplasm
- Chromatin degradation
- Cellular degradation due to loss of function (blebbing)
- Apoptotic bodies, which then are taken up by phagocytes
Necrosis
- Not caused by CD8+ CTL
- Caused by external factors such as infections, toxins, trauma
- Induces inflammation
CD4+ T helper cells
- Provide help to other immune cells by secreting cytokines
- The help gets those cells going and results in specific type of immunity (regulates immunity type)
- Express TCR and CD4+
- Begin life as naïve T cells in lymphoid tissues, when they are activated, they become Th0 cells which have a potential to become many other type of Th cells
What types of Th0 (t helper cells) can the CD4+ T cells become?
Depending on signal 2 (co-stimulatory) and signal 3 (cytokine) provided by APCs, the Th0 can become
o Th1
o Th2
o Th17
o T regulatory (Treg)
o Follicular T helper
Purpose and Formation of Th1
- Needed against intracellular pathogens
- Th0 releases IL-12, IFNg to produce Th1
Purpose and formation of Th2
- Needed against extracellular pathogens
- Th0 releases IL-2, IL-4, IL-5, IL-13 to produce Th2
Purpose and formation of Tfh
- Needed for B cell differentiation
- Th0 releases IL-6, IL-21 to produce Tfh
Purpose and formation of Th17
- Needed for extracellular infection at mucosal sites
- Th0 releases IL-6, TGF-b to produce Th17
Purpose and formation of Treg
- Needed for suppression of immunity
- Th0 releases IL-2, TGF-b to produce Treg
What does Th1 release?
- IL-2
- IFNg
- TNFa
- TNFb
What does Th2 release?
- IL-4
- IL-5
- IL-13
What does Th17 release?
- IL-17
- IL-21
- IL-22
What does Tfh release?
- IL-21
- IL-17
What does Treg release?
- IL-10
- TGF-b
- IL-35
