Theme 4 - 4b (T cell activation pt 2 and T cell effector functions) Flashcards
what determines what specifc T helper cell a T cell will becomes
cytokines produced by APCs
what generally do T helper 1 cells do
mediate cell mediated immunity
what generally do T helper 2 cells do
mediate humoral immunity
what effect does signal 3 (polarising factors) have on the T cell
- induces TF activation
- causes T cells to produce different things eg T H 1 cells prod INTERFERON GAMMA and T H 2 produces IL4,5.13
how does CROSSREGULATION occur
- activation of ONE TF and thus development of TH1/TH2 cells will INHIBIT the development of th eother type of immune response
what is the master regulatory TF for TH1 cells?
T-Bet (activation of T-Bet inhibits activation of GATA-3)
what is the master regulatory TF for TH1 cells?
GATA-3 (activation of GATA-3 inhibits activation of T-Bet)
is the T H subset fixed
no, it can change as the immune response develops
do CD8+ T cells need MORE or less stimulation than TH cells to be activated
MORE (as they are cytotoxic)
- this is provided by CD4+ T helper cells (Th1 or Th17) that have recognised antigen on the APC
- the activation from CYTOKINES (IL-2) released from CD4+ T cells
- CD4+ T cells also ACTIVATE DCs via C40 TO CD40 ligand activation, this makes the DC BETTER at activating the CD8 T cell
what is the effect of CD40
- CD40L binds to CD40 on the APC, which stimulates it to make more co-stimulatory CD80/CD86 O ENHANCING activation of the CD8 T cell
in CD8+ T cell activation, what causes activation of CD4 T cells
the dendritic cell activates both CD8+ and CD4+
T cells must be activated by what
- by RELATED ANTIGENS presented by BOTH MHCI and MHCII on the SAME APC
what % of MHC class I molecules present peptides from EXOGENOUS antigens
25%, this is a process that isnt understood well
what is cross presentation
what is it important for
the presentation of EXOGENOUS antigens on MHC class I by unknown mechanism
- paramount for the activation of CD8+ T cells
what is cross presentation
what is it important for
the presentation of EXOGENOUS antigens on MHC class I by unknown mechanism
- paramount for the activation of CD8+ T cells
TH1 cells are involved in what type of mmune response
cell mediated immune responses (fighting INTRACELLULAR pathogens eg things taken up by macrophages or viruses in cells)
TH1 cells can interact with macrophages using WHAT LIGAND
where does this occur
CD40 LIGAND (CD40 L ) on T cell interacts with CD40 on APC induces macrohphage to be BETTER AT KILLING the microbe it has phagocytosed
- occurs in the PERIPHERAL tissue, where the infection actually is
TH1 cells can interact with macrophages using WHAT LIGAND
where does this occur
CD40 LIGAND (CD40 L ) on T cell interacts with CD40 on APC induces macrophage to be BETTER AT KILLING the microbe it has phagocytosed
- occurs in the PERIPHERAL tissue, where the infection actually is
what is the effect of Th1 cells at the periphery (that uses NEUTROPHILS)
- NEUTROPHILS are activated using TNF alpha (increased inflammation and microbial killing)
how do Th1 cells activate NK cells and CD8+ T cells
Th1 cells produce INTERFERON GAMMA which activates NK cells and CD8+ T cells which helps kill virally infected cells
what is the role of Th1 cells in the secondary lymphoid tissue
- produce INF-gamma which acts on B cells causing them to produce different IMMUNOGLOBULINS (IgG3 and IgG2a) which INC OPSONISATION and PHAGOCYTOSIS of microbes
- O allowing the macrophages to engluf the microbes more easily
briefly summaraise the 4 effector mechanisms of Th1 cells
1) in 2ndary lympohoid tissue, they release IFN-gamma which causes B cells to produce IgG3 and IgG2a which inc OPSONISATION and PHAGOCYTOSIS of microbes
2) in the PERIPHERY NEUTROPHILS are activated using TNF alpha (increased inflammation and microbial killing)
3) in the PERIPHERY CD40 LIGAND (CD40 L ) on T cell interacts with CD40 on APC induces macrophage to be BETTER AT KILLING the microbe it has phagocytosed
4) produce INTERFERON GAMMA which activates NK cells and CD8+ T cells which helps kill virally infected cells
what immune response do Th2 cells promote
humoral immune response
Th2 cells interact with B cells causing what
where does this occur
- in the secondary lymphoid tissue
- CD40L on Th2 binds to CD40 on B CELL
- and IL-4 production causes
- this causes the production of neutralising IgG antibodies (IgG4 human and IgG1 in mice) IMPORTANT for binding to SMALL soluble particles eg TOXINS so they can be NEUTRALISED
- also causes the production of IgE which is important in MAST CELL DEGRANULATION which can bind to PARASITES and HELMINTHS
what effect do Th2 cells have on IL-5
- Th2 cells release IL-5 causing ACTIVATION of EOSINOPHILS which can RECOGNISE OPSONISED HELMINTHS/PARASITES
are the released factors of mast cells and eosinophils targeted/general
GENERAL: O they can act on self cells as well, which are responsible for causing the ‘allergic’ reaction
how can Th2 cells essentially turn off the Th1 cell response
- by releasing IL-10 and IL-4 which act in the PERIPHERY to cause the SUPRESSION OF MACROPHAGE ACTIVATION
briefly summarise the effector mechanisms of Th2 cells
1) in 2ndary lymphoid tissues the binding of CD40L to CD40 on B CELLS as well as IL-4 production causes the production of NEUTRALISING IgG antibodies (which target small things eg TOXINS) and production of IgE which causes MAST CELL DEGRANULATION–> HELMINTHS/PARASITES
2) release IL-5 in the PERIPHERY ACTIVATION of EOSINOPHILS which can RECOGNISE OPSONISED HELMINTHS/PARASITES
3) releasing IL-10 and IL-4 which act in the PERIPHERY to cause the SUPRESSION OF MACROPHAGE ACTIVATION
what is the role of Th17 cells
they are important in protection against bacteria in MUCOSAL SURFACES (eg gut)
- eliminate extracellular bacteria and fungi
explain in detail what effect
- in the 2ndary lymphoid, the effector cells then move to the PERIPHERAL to the MUCOSAL surface
- here they release IL-17 and IL-22
- IL-17 is a potent inducer of INFLAMMATION and causes NEUTROPHILS to be attracted to the site
- neutrophils then clear the bacteria (O help epi produce antimicrobial peptides)
- IL- 22 also helps the epi prod antimicrobial peptides
- it INCREASES the BARRIER function of EPITHELIAL surface O there are fewer leaks O bacteria cannot enter tissue
what is the role of the Tfh cells
what do they develop with
- can ACTIVATE B cells to PROLIFERATE and DIFFERENTIATE into Ab
- develop in concert with Th1, Th2 and Th17 cells
what is class switching and what do Tfh have to do with it
CLASS SWITCH: They help B cells to generate different Ig isotypes and undergo affinity maturation in the germinal centre
which Ig isotype and O FC receptor depends on what
depends on the most appropriate innate immune effector interaction
why are Tfh cells unlike the other Th cells
unlike Th1, Th2 and Th17, Tfh cells contribute to the eradication of most classes of pathogens
O involved in ALL TYPES OF IMMUNE RESPONSES
where do all the functions of Tfh occur
in 2ndary lymphoid organs, as they direct the B cell response
how do Tfh cause class switching
- B cell binds Ag and take it up (phagocytose)
- then present via MHC II to Tfh
- Tfh via CD40L and IL-21 ACTIVATE B cell and make it produce diff type of Ig and CAUSE ISOTYPE SITCHING AND AFFINITY MATURATION
give example of responses that Tfh are involved in
explain why
- allergic response
- cell mediated response
- Th17
as it CHANGES what AB (via class switching) are produced
where do Tregs (T regulatory cells) work
2ndary lymphoid and periphery
what are the functions of Tregs
1) produce ANTI-INFLAMMATORY cytokines
2) provide CTLA-4 which engages CD8-/86 during ANERGY
3) Tregs ‘rip off’ and ENDOCYTOSE CD80/86
which inflammatory cytokines does Tregs produce
- TGF beta
- IL-10
why is CTLA-4 important
- CTLA-4 is expressed on the naive T cell
- it interacts with CD80/86 INSTEAD of C28
- O BLOCKS the co-stimulatory signal, and you dont get activation of an effector response
how can Tregs affect CD80/86
- they can rip off and ENDOCYTOSE CD80/86
which cytokines does Th1 release
IFN gamma
which cytokines does Th2 release
IL-4, Il-5
which cytokines does Treg release
IL-10, TGF beta
which cytokines does Th17 release
IL-17
which cytokines does Tfh release
IL-21
what are the key Th cells
1,2,17, fh and Treg
how are T cells in circulation directed to the right part of the body
by the interaction between MOLECULES ON T CELLS and on ENDOTHELIAL CELLS lining the blood vessels
what is the role of cytokines in T cell migration
- produced by the innate immune system
- the UPREGULATE ADHESION MOLECULE EXPRESSION on the endothelium to INITIATE MIGRATION
what are chemokines
a type of cytokine that attracts cells to PARTICULAR SITES
where do CD8 + T cells carry out their functions
at the periphery, at the exact place that pathogens are
what directs whether a T cell needs to go to the periphery or to the lymph node
chemokine gradients
what are thesteps in T cell migration
1) start with ROLLING, LOOSE adhesion, controlled by SELECTINS
2) then the CHEMOKINES cause ACTIVATION of intergrins on T cell (a more FIRM interaction between endothelium and T cell)
3) there is then a STABLE ARREST guided by INTEGRINS
4) then the T cell follows the CHEMOKINE GRADIENT
5) there is then EXTRAVASATION/MIGRATION
what is T cell migration directed by
adhesion molecules
where do naive T cells need to migrate between
between lymph nodes where they may come into contact w/ APCs
O to enter the lymph node they need to pass the HEV
to enter to HEV what selectins, chemokines, integrins and chemokines does the naive T cell express
- L-selectin
- CC21 chemokine
- LFA-1 integrin
- CC21, CC12 chemokines
where do the effector T cells need to enter
they need to enter the infected tissue
which selectin, chemokine and integrins do effector T cells use
- E and P-selectin
- CXCL10 chemokines
- LFA-1 and VLA-4 integrin
when and why do T cells alter their adhesion molecule expresion
AFTER ACTIVATION to an EFFECTOR CELL and differentiation (because effector cells need to go to the site of infection)
what determines adhesion molecule expression on T cells
- partly determined by the APC
- O the APC helps direct the effector T cell to correct tissue
what are the 4 key steps of T cell migration
1) rolling
2) activation by chemokines
3) adhesion
4) extravasation
what mediates T cell migartion
1) selectins (rolling)
2) integrin (firm adhesion)
3) chemokines
4) integrin activation
CD8 T cell killing is what
SPECIFIC: target cell must bear the SAME antigen that activated the naive CD8 + T cell presented in MHC I on its surface
CD8+ T cell must CONTACT the target cell
CD8+ T cells REMAIN INTACT after they kill target cells, each is capable of killing may target cells
what is CTL
cytotoxic T lymphocytes
how does a CD8+ cell cause cell death
- causes DNA FRAGMENTATION
what are the 2 mechanisms used by CD8+ to induce cell death
1) GRANZYME/PERFORIN granules (used most commonly)
2) Fas-Fas ligand
describe GRANZYME/PERFORIN granules as a method of killing used by CD8+ T cells
1) MHC I and TCR interact forming IMMUNOLOGICAL SYNAPSE
2) causes release of granules which act ONLY on the target cell
3) perforin punches a hole in the bilayer, allwoing granzymes into the cytosol, which…
4) causes CASPASE activation
5) causes APOPTOSIS
describe Fas-Fas ligand as a method of killing used by CD8+ T cells
1) Fas ligand on T cell interacts w/ Fas on target cell
2) causes CASPASE activation
3) causes APOPTOSIS
why is it important that CD8+ T cells kill and induce detah via APOPTOSIS and NOT NECROSIS
- necrosis can cause uncontrolled release of material (you are exposing pathogen to healthy tissue)
- apoptosis is controlled
what is the TCR, antigen, MHC, location, main target, and function of γδ T cells
TCR: γδ
ANTIGEN: non peptide, lipid
MHC: independent (like PRR)/MHC like proteins
LOCATION: skin, mucosal lymphoid tissue, blood
MAIN TARGET: Bacterial infections, pathogenic toxins, stress markers
FUNCTION: Cytotoxicity (perforin/granzyme) and cytokines (IFNγ, TNFα and IL-17). Can phagocytose
what is the TCR, antigen, MHC, location, main target, and function of iNKT T cells
TCR: iα:β
ANTIGEN: Microbial lipid
MHC: CD1
LOCATION: Mucosal surface
MAIN TARGET: Infected/ transformed cells (low does bacterial infections
FUNCTION: Cytotoxcity (mainly Fas:FasL) and cytokine (e.g. IL-2/TNFα
what is the TCR, antigen, MHC, location, main target, and function of general T cells
TCR: α:β
ANTIGEN: peptide
MHC: MHC I/II
LOCATION: Lymph, peripheral tissue, blood
MAIN TARGET: infected/transformed cells
FUNCTION: Cytotoxcity (perforin /granzyme and Fas:FasL) and determining immune response (cytokines)
γδ and iNKT T cells are innate or adaptive?
somewhere in between
what are the 5 stages of T cell response
1) antigen recognition
2) activation
3) antigen elimination
4) contraction/homeostasis
5) memory
what happens during contraction/homeostasis
- stimulus for co-stimulation DEC
- new effector cells are NOT activated
- effector cells AGE and die by apoptosis and are cleared by PHAGOCYTES
(alost 95% of T cells die once antigen is eliminated)
what happens to the effector T cells that are not killed by apoptosis
some stay in lymph node, some stay in peripheral tissue
how do memory T cells form
- Some of the progeny of antigen-stimulated T cells develop into long-lived, functionally quiescent (‘resting’) memory cells
- Memory T cells are responsible for accelerated and enhanced secondary immune responses on subsequent exposures to the same antigen
which cytokines are req for polarisation of Th17
IL-1, IL-6, TGF BETA
