Lecture 10+11: T Cells Flashcards
Where do all lymphocytes development from
Hematopoietic stem cells
What is responsible from getting lymphocytes from HSC to lymphocytes
Stromal cells and cytokines
Where does T cell development occur
Thymus
Where do T cell progenitors originate
Bone marrow
What dictates movement of lymphoid progenitors to thymus
Chemokines
What cytokine is critical to development and commitment to T cell line
IL-7
What is IL-7 made by
Thymic stromal cells
Mutations in IL-7 lead to
No T cells
What do double negative thermocytes express to commit to T cell lineage
CD3 and CD5-adhesion and signaling molecules
Describe the role of Notch 1 and commitment to T cell lineage
Receptor for Notch 1 is on thymocytes, without notch 1 won’t transcribe for T cell lineage, once Notch 1 binds it cleaves repressors with proteases and activates T cell associated genes
What are the two T cell lineages
Gamma:delta
Alpha: beta
TCRs interact with linear peptides T or F
True
What do gamma:delta T cells express and where are they found
Express only CD3 and found in gut mucosa
What do Alpha:beta T cells express
CD4, CD8 and CD3
Which allele (gamma, delta or Beta) rearrangement increases likelihood to commit to T cell line
Beta allele rearrangement
What happens to T cells that do not make productive arrangements
Die by apoptosis
What percentage of T cells survive by making productive arrangement
2%
How many attempts do each B allele get to make successful rearrangement
2
How many total attempts for B chain rearrangements on chromosome
4
What genes are responsible for recombination
RAG1 and RAG2
Describe the steps in forming the Pre-T cell receptor
Ptalpha (invariant chain) checks the functionality of the Beta chain
If functional heterodimers form superdimer
Superdimer checks for interaction with CD3
Initiates rearrangement of alpha chain
Synthesizes CD8 and CD4
Proliferation of pre-T cell line
First T cell checkpoint
What genes are responsible for rearrangement of alpha chain in pre-t cells
RAG 1 and RAG2
What happens if rearrangement makes a functional alpha chain
Alpha chain is translocated into ER to check for interaction with B chain
Line proliferates
2nd T cell checkpoint
Combinatorial diversity
Separate rearrangement events for alpha and beta TCR chains so get diversity from that and how they interact, dictates antigen binding
Omenn syndrome
RAG deficiency lack T cells and B cells, opportunistic infections, must treat with bone marrow transplant or fatal
What is the first checkpoint in T cell development
After B genes rearrange
What is 2nd checkpoint for T cell development
After alpha genes rearrange
What is positive selection
Checks for TCR binding to MHC complexes
Weak or no binding- die
Strong moderate binding- live
Where does positive selection occur
Cortex of thymus
What determines CD4 and CD8 expression
Positive selection, receptor will either bind MHC I or MHCII
What is negative selection
TCR must recognize MHC complex but not bind too well, if it binds tightly to APC in thymus it undergoes apoptosis
At what point can a T cell migrate to secondary lymphoid organs
After undergoing negative selection and not tightly binding to MHC
What is CD28
Co-stimulatory molecule
What is CTLA-4
Inhibitory signal
What are the adhesions molecules in T cells
Integrins-LFA-1, VLA-4
Generation of mature T cells occurs in stages that are defined by ____
Certain proteins expressed on cell surface
What occurs in progenitor (pro-T cell) stage
Proliferation and initiation of somatic recombination of Beta chain
What occurs in precursor (pre-T cell) stage
Expression of B chain with surrogate alpha (pTalpha) and CD3 and zeta chains=Pre-TCR complex
What makes up the Pre-TCR complex
CD3 and zeta chains, PTalpha, Beta chain
What happens in double positive T cell stage
Alpha and beta chains successful rearranged and expressed along with CD3 and zeta chains as membrane bound BCR complex
Express CD4 and CD8
Positive and negative selection occurs
What happens in single positive T cell
Downregulation of either CD8 or CD4 and final maturation occurs
What happens a mature, naive T cell right after development ends
Released into circulation as single positive T cell
What happens when naive T cells encounter their antigen
Induce T cells to proliferate and differentiate, effector T cells perform function
How is delivery of antigen to lymphoid tissues aided by innate immunity
Dendritic cells deliver to lymphatic vessel, inflammation increases blood flow to infected sites as well as lymph
How do T cells enter lymph nodes
HEV or lymphatics from upstream lymph node
How do T cells find their antigen
Naive T cells come from blood stream, migrate to peripheral lymph tissue and sample peptide: MHC complexes on dendritic cells
What happens to naive T cells that don’t find their antigen
Exit issue and reenter blood- continual process of circulation
What happens if T cells recognize antigen
Migration ceases, clonal proliferation and differentiation, give rise to memory and effector cells
Activated T cells reenter blood stream
When can and can’t T cells exit lymph node
Once T cell is activated by antigen it must proliferate and can’t exit at that time, once proliferated those activated/effector T cells can exit
Antigens in blood are carried by ___ to ___
APC’s to spleen`
Pathogens in other sites are transported in ___ to ____
Lymph to regional lymph node
Pathogens on musical surfaces are carried across mucosa and into ___ or ____
Tonsils or Peyers patches
Describe the steps in how T cells enter lymph nodes/leave HEV
Circulating lymphocyte enters the HEV in lymph node
Binding L-selection, GlyCam-1 and CD34 allows rolling interaction
LFA-1 is activated by chemokines bound to ECM
Activated LFA-1 binds tightly to ICAM-1
Lymphocytes migrates into lymph node via diapedesis
Is LFA-1 and L-selectin present on lymphocyte or HEV
Lymphocyte
Is GlyCAM-1, ICAM-1 and CD34 on lymphocyte or HEV
HEV
Where are dendritic cells located
Throughout body
Where are macrophages located
Lymphoid tissue, connective tissue, body cavities
Where are B cells located
Lymphoid tissue, peripheral blood
What is the effect of activating dendritic cells
Results in activation of naive T cells
What is the effect of activating macrophages
Activate macropahges
What is the result of activating B cells
Delivery of help to B cells, antibody production
During rolling interaction and binding if T cell finds antigen what happens
Induce conformational change in LFA to increase binding affinity
What are the three signals for clonal expansion and differentiation in activating naive T cells
Signal 1- TCR:MHC binding (not enough)
signal 2-costimulatory signals promote survival and expansion of T cell clones (ex: B7 expressed on T cell binds CD28 on DC
Signal 3: cytokines direct T cell differentiation into different types of effector T cells
Despite self testing on T cells in thymus some make it through, peripheral cells and non-activate dendrites do not express
Co-stimulatory molecules and Naive T cells don’t get activated
Co-stimulatory signal alone, effect on T cell
No effect on T cell
Antigen specific signal alone effect on T cell
Inactivation (anergy) or deletion of T cell
If there is successful TCR:MHC binding what are the three survival transcription factors
NFAT, NFKB, AP1
What cytokine is synthesized to promote survival and activation of naive t Cells
IL-2
What does CD69 do
Retains stimulated T cell in lymph node for clonal differentiation and expansion
What is S1P
Chemoattractant that is high in the blood and low in tissues.
Do circulating naive T cells have high or low expression of S1P receptor
Low
T cells not stimulated by antigen ____S1PR1
Reexpress which allows naive T cells to respond to S1P gradient and exit lymphatic tissue
What happens when CD69 binds S1PR1
Cells internalized the complex and turn off S1PR expression, T cells in activation proliferate and differentiate and can’t leave
What retains naive T cell in lymph node
CD69
What causes proliferation of activated T cell
Express IL2 and IL2R via costimulatory signals with CD28
What cytokine is critical for differentiation of T cells into effector and memory cells
IL-2
Describe the steps in formation of IL-2R
Naive T cells express IL2 receptor gamma and betta, activation of these T cells leads to expression of alpha portion and induces proliferation
What does cyclosporine do
Binds to cyclophilin within the cell and inhibits calceneurin preventing NFAT generation, without NFAT, transcription of IL-2 won’t occur which is necessary for T cell proliferation
What is the ligand and receptor responsible for effector function of naive T cells
CD40 and CD40L
Describe the relationship between CD40, CD40L and T cells
Activated T cells express CD40L which bind CD40
Leads to activation of macrophages-Th1 cell infected macrophage come together by binding CD40 and CD40L as well as MHCII and TCR and result in killing of intravesicular bacteria
Leads to activation of B cells to produce antibodies
What is Hyper IgM syndrome
CD40/CD40L deficiency that doesn’t allow antibody class switching, no activation of macrophages
what is CTLA-4
Inhibitory signal, binds B7 on APC to limit T cell proliferation, blocks CD28 signaling
What are short lived cells for immediate immune response
Effector T cells
what are long lived ells that respond to later infection with rapid, strong response, make new effector and memory cells
Memory cells
What must be produced in order to continue survival of memory T cells
IL-7
Describe steps of dendritic cell presenting to strong CD8+ T cell
Dendritic cell presents to naive T cell, dendritic cell sends sufficiently strong signal to activate CD8+ T cell effector status, activated T cell makes IL-2 to drive its own proliferation
Describe steps when dendritic cell presents signal to weaker CD8+ T cell
Dendritic cell activates CD4+ T cell to help and secrete IL-2 and CD8+ T cells express IL-2 receptors, IL-2 from CD4+ drives clonal differentiation and proliferation of CD8+ T cell
Once CD8+ Cells are activated how do they kill host cells
Apoptosis by releasing toxic granules
What toxic granules do cytotoxic T cells have
Perforin-pore forming protein that allow granzymes to enter which are serine proteases that activate capsases in host cells to trigger apoptosis
What cytokine produces Treg cells
TGF-B
what cytokine produces TfH cells
IL-6
What cytokines activate Th17
IL-6 and TGF-B
What cytokines activate TH1
INF-y and IL-12
What cytokine activate Th2
IL-4
What is the role of TH1
Control bacteria that grow in macrophages, express INF-y and IL-2
What is the role of Th2 cells
Control parasitic infection, express IL-4, IL-5, IL-13 that promote mast cells, eosinophils and B cell class switching to IgE
What is the role of Th17 cells
Stimulate neutrophil response to extracellular bacteria and fungi
What is the role of TfH cells
Stimulate antibody production from B cells including class switching and affinity maturation
What does Treg do
Regulate immune response
What bacteria can grow inside macrophage and phagosome, avoid detection by antibodies and CD8 T cells, inhibit fusion of phagosome and lysosome
Mycobacterium
What stimulates macrophage and boots antimicrobial mechanisms
IFN-y and CD40 ligand
What happens once macrophage is activated by TH1
Fusion of phagosome with lysosome and form reaction oxygen and nitrogen species
Why not always have macrophages activated
Energy costly and reactive oxygen and nitrogen species can cause damage to host cells and tissues
What drives Th2 cell differentiaiton
IL-4 in response to helminths and allergens
What happens when activate Th2 in response to helminths
Mast cells secrete IL-4,
What does IL-4 stimulate
B cell class switching to IgE
What does IL-5 activate
Eosinophils
What does IL-4 and IL-13 stimulate
Increased mucus secretion
What drives Th17 differentiation
Pro inflammatory cytokines and TGF-B
What does IL-17 do
Stimulates recruitment and production of neutrophils
What does IL-22 do
Promotes epithelial integrity, antimicrobial peptides and mucin
