T Cell Mediated Immunity Flashcards
CD4+ T cell broad function
Help activate B cells and macrophages
CD8+ T cells broad function
Initiate cell death of infected or transformed cells
Which type of cell can DCs activate?
Mature naive T cells
Which type of cell can B cells and macrophages activate?
Memory T cells
Characteristics of activated peripheral DCs
Lose adhesive markers and upregulate CCR7 expression (lymphatic endothelium)
Increase expression of MHC, CD80 (B7) and LFA-1
Mature as they migrate to regional secondary lymphoid tissue
Home by chemokines
Present Ag to mature naive T cells circulating in lymph tissue
Which cytokines are secreted by DCs in order to promote T cell subset differentiation?
IL-12: Th1
IL-23: Th17
IL-10: Tregs
What do T cytotoxic cells express on their surface?
TCR/CD3 signaling complex including zeta
CD8+, MHC class I
CD28+, CCR7
LFA-1 and L selectin
What do T helper cytokine secreting cells express on their surface?
TCR/CD3 signaling complex including zeta
CD4+, MHC Class I
CD28+, CCR7
LFA-1 and L-selectin
Describe naive T lymphocyte trafficking
Naive T cells enter the LNs across HEV in the cortex
Slow down - L selectin and CCR7
Stable arrest - LFA
T cells sample the Ag presented by APCs and will either proliferate and differentiate into effector cells or wont encounter the Ag and leave the LN through the lymph and travel down the chain to the next LN
Describe the immunological synapse for CD4 T cells
CD4 —> MHC class II TCR —> peptide presented on the MHC class II CD3 ITAM CD28 and CTLA4 —> B7-1/-2 (CD80) PD1 ITIM —> PD-L1/L2 LFA-1 —> ICAM1 (adhesion)
What is the first signal for T cell activation?
Binding of MHC/peptide complex displayed by DC to TCR on the T cell
What is the second signal for T cell activation?
Recognition of the Ag is critical for the upregulation of co-stimulatory molecules
Binding of the co-stimulator molecules provides second signal to the cell
What other cellular changes occur when the TCR/HLA recognizes an Ag?
Recognition changes integrin conformation on T cells from low affinity to high affinity
Integrin avidity increases upon Ag recognition by T cells: LFA-1
Allows for clustering of adhesion molecules and firm adhesion for immune synapse
What happens upon binding of the TCR to MHC/peptide complex during T cell activation?
Upon binding of TCR to MHC/peptide complex the T cell increases CD40L expression and CD28 expression is constitutive
DC has CD40 constitutive expression while B7/CD80 expression and cytokine secretion is increased
Why is T cell activation a two pronged approach?
Clonal selection
First signal: recognition of antigenic epitope by TCR
Second signal: maintains the specificity of the response to the specific epitope
This results in a large number of Ag-specific effector cells from rare Ag-specific naive T cell
When does induction of anergy occur?
T cells recognizing Ag without binding of co-stimulators ligands or cytokine support will not become activated
Instead they become unresponsive to additional stimulus (anergic and tolerant)
Describe T cell activation
Formation of the immune synapse initiates the intracellular signaling leading to complete T cell activation and occurs through activation of ITAMs
Kinase associated with coreceptors CD4 and CD8 phosphorylates and activates the tyrosine kinase ZAP-70 associated with the zeta chain
Activation of ZAP-70 on the zeta chain is necessary for all downstream signaling
Describe the cascade of protein production that occurs after activation of T cells?
Substantial proliferation of activated lone to expand population of Ag specific lymphocytes
Activated CD4+ Th cells start expressing CTLA4 and PD1 for immune regulation
Activated CD8 T cells start expressing PD1 for immune regulation
Explain the order of receptor expression during an immunological response
C-Fos —> CD40 ligand —> IL-2 —> IL-2a (CD25) receptor —> DNA synthesis
IL-2 is an
Autocrine survival signal for newly activated T cells and is not produced until T cell activation
IL-2R-beta-gamma-c is constitutively expressed on what?
Mature a naive T cells as a low affinity receptor minimizing proliferation
What happens when IL-2 binds to its receptor?
Upon activation upregulation of additional high affinity chain in IL-2R alpha chain occurs (IL-2R-alpha-beta-gamma-c
Binding of IL-2 to high affinity IL-2R promotes T cell differentiation and proliferation
Within two days of an Ag appearing in a LN it has been bound by its
Naive Ag specific T cell
5 days after the arrival of the Ag, activated
Effector cells emigrate from the LN into the periphery
Where is S1P highly present in the body?
Blood and lymphatic
Explain the role of CD69 in T cell sequestering
Naive T cells express S1PR that directs their migration through the circulation
Newly activated T cells will transiently express CD69
CD69 binds to S1PR on T cell surface and sequesters it
Leaves the T cell unable to respond to S1P migration signals
Ensures activated T cell has time to provide help to other lymphocytes
New effector cells lose CCR7 and upregulate S1P —> effector cells cross endothelial barrier and enter circulation in response to S1P
What do all CD4+ T helper cells start out as?
Th0 cells
Differentiation of each T helper cell subset is induced by what?
The type of microbes it is best able to combat
Ag drives the response and the contributing cytokine microenvironment during activation
Each subset of T helper cells produces what?
Cytokines that support its own development and suppress other subset development
Describe how CD4 T cells help CD8 T cell activation
Cytokine support of activation and proliferation of CTLs
Induction of cytotoxic protein synthesis
Cross presentation is often necessary for CD8 T cell activation
Characteristics of CD4+ Treg cells
Influenced by IL-2, IL-10 and TGF-beta Constitutively express CTLA4 and CD25 (alpha chain) Novel TF FOXP3 Secrete IL-10 and TGF-beta Peripheral tolerance
Where are gamma delta T cells found in high numbers?
At epithelial boundaries especially the gut mucosa
What do effector T cytotoxic and helper cells express on their surface?
TCR/CD3 signaling complex including zeta CD8/CD4, MHC class 1 CD28+, CD25+, PD-1 LFA-1/VLA-4, CXCR3 E and P selectin ligand FasL (CD8 T cells) CTLA4 (CD4 T cells)
What is the major difference between effector T cells and resting naive T cells?
An effector T cell is able to respond to specific Ag without the need for co-stimulation via B7 (CD80)-CD28 interaction
How are the adhesion molecules and chemokines for effector T cells expressed at the site of infection different from the molecules on HEVs that naive T cells interact with?
Slow down: E and P selectin ligand and CXCR3
Stable arrest: LFA1 and VLA-4
Characteristics of Th1 cells
Secrete IFN-gamma and TNF-alpha
Role: classical macrophage activation
Defense: intracellular pathogens
Pathology: chronic inflammation and autoimmunity
Characteristics of Th2 cells
IL-4, IL-5 and IL-13
Role: eosinophil, mast cell and alternative macrophage activation
Defense: helminthes
Pathology: allergy
Th17 cell characteristics
Secrete IL-17 and IL-22
Role: neutrophil activation
Defense: extracellular bacteria and fungi
Pathology: autoimmunity and inflammation
Treg cell characteristics
Secrete IL-10 and TGF-beta
Role: peripheral tolerance
Defense: regulation of T cell response
Pathology: autoimmunity
Th1 cells proliferate in response to which cytokines?
IL-12 and IFN-gamma secreted by macrophages, NK cells and DCs
Th1 cell cytokine (IFN-gamma) activities
Classical activation of macrophages for killing of microbes
Stimulates B cells to class switch to IgG during activation (opsonization)
Stimulates class II HLA Ag presentation and B7 expression*
Inhibits Th2 and Th17 production
What do Th2 cells proliferate in response to?
IL-4 secreted by mast cells, basophils andTh2 cells in immediate surroundings
What is the unique TF for Th1 cells?
T-bet
What is the unique TF for Th2 cells?
GATA-3
What the activities of the cytokines secreted by Th2 cells (IL-4, 5 and 13)?
Stimulates B cells to class switch to IgE during activation
Increased production of mucus in epithelial cells (IL-13)
Increased eosinophil migration and activation (IL-5)
Support alternative macrophage development
Th2 cells function as protection against helminths through what?
Mast cell activation, mucus production, peristalsis, IgA production and eosinophil activation
What do Th17 cells proliferate in response to?
IL-1 and IL-6
What is the unique TF for Th17 cells?
RORyt
IL-17 activity
Inflammatory
Recruitment of pro-inflammatory leukocytes
Increases pro-inflammatory cytokines and chemokine production
Stimulates anti-microbial peptide (defensins) production
IL-22 activity
Protective
Promotes regenerative responses with epithelial barrier
Stimulates anti microbial peptide (defensins) production
Th17 cell immunity
Important in barrier function integrity
Role in inflammatory autoimmune diseases including MS, IBS and RA
Role in integument pathology and cancers such as breast/lung
What is the effector function of CTLs?
Killing of cells infected with intracellular pathogens or tumor transformed cells by release of lytic enzymes or Fas/FasL induced cell death
What effect do Th1 effector cells have on CTLs?
Enhance proliferation, differentiation and clonal expansion of activated CD8+ T cells by providing additional IL-2
Why dont CD8+ T cells need CD40/40L and CD28/B7 lignad interactions that are seen with effector Th1 cells and macrophages?
Because the CD8 cells need to be able to kill any infected cell in the body not just APCs
Which cells are considered tumor surveillance cells?
NK cells and CD8 T cells
What are the two killing mechanisms for CD8 T cells?
Cytotoxins (perforin and granzymes)
Fas/Fas induction of apoptotic pathways in target cell s
Where do CD8+ T cells perform their specific functions?
In the periphery, not in lymphoid tissues where they were activated
What is the killing pattern of CTLs?
Ag specific recognition of infected/transformed cells
Induction of apoptosis to prevent pathogen replication and release of infectious material
Move to the next target cell
Why are two different recognition systems necessary for transformed/infected cells?
Some intracellular pathogens and cancers downregulate expression of MHC class I
Describe Ab dependent cell mediated cytotoxicity (ADCC)
NK cells, macrophages, neutrophils and eosinophils
Targeted recognition through IgG or IgE binding
Killing by lytic enzymes, TNF and perforin/granzyme by specific cell types
As the antigenic stimulus is removed during an immune response what happens to the effector T cells?
The majority of effector T cells undergo apoptosis
A small percentage of clones will become memory cells and express increased levels of anti-apoptotic protein Bcl-2
Function of CTLA4 on Treg cells
CTLA4 binds to B7 co-stimulatory ligand on APC and competitively block APC signaling
Binds more avidly than CD28
Describe effector T cell exhaustion
Regulatory ligand expression can also lead to inability of T effector cells to respond effectively to chronic infections
Effector cells become exhausted as they express increasing amounts of PD1 and CTLA4 on the cell membrane
Characteristics of memory CD4 and CD8 T cells
Require re-activation to regain effector function
Respond more rapidly than naive
Can respond in peripheral tissues
Require IL-7 and IL-15 for survival
Describe some evasion mechanisms
Pathogens have adapted to escape our immune processes
Viruses and intracellular pathogens can downregulate the cell mediated immune responses by several different mechanisms
Some are overlapping mechanisms and others are pathogen specific
Most are related to Ag processing or cytokine driven
