Lecture 10+11: T cells Flashcards
where do B, T and NK cells derive from
hematopoietic stem cell –> multipotent progenitor cell —> common lymphoid progenitor cell
where does T cell development occur
in the thymus
T cell progenitor cells originate in _______ and migrate to the thymus
originate in bone marrow
*movement dictated by chemokines
what directs the movement of T cell progenitors from bone marrow to thymus
chemokines
- receive signal from thymic stromal cells to differentiate into thymocyte
what interleukin is incredibly important to T cells so much so that mutations of this IL leads to no T cells
IL7
lymphocyte development (B,T and NK cells) is orchestrated by what cells and messengers
stromal cells and cytokines
mature T cells leave the thymus and travel to…
secondary lymphoid tissue
if a patient is unable to make IL7, what happens
they cannot make T cells = no adaptive immune response
what cells make IL7
thymic stromal cells
what is notch1, what does it do
Notch1 is a receptor on thymocytes that binds to thymic epithelium
it induces cleavage by protease & activates T cell-associated genes
*induces the expression of genes associated w/ activation of T cells
what are the 2 classes of T cell receptors?
gamma delta (γδ) - CD4/CD8
alpha-beta (αβ) (binds things other than CD4/CD8)
______ interact w/ folded proteins, _____ interact w/ linear peptides
Antibodies - folded proteins
TCR - linear
γδ T cells only express ____
CD3
what occurs at T cell checkpoint 1
- A pre-T cell receptor pairs a β chain w/ pTα
- pTα checks the functionality of the β chain
- if functional, forms a superdimer
-superdimer checks for interaction w/ CD3
-if there is appropriate interaction w/ CD3, that β chain starts to proliferate, initiates rearrangement of the α chain, and synthesis of CD4/CD8 begins
The rearrangement of α chains in pre T cells is mediated by what
RAG 1 and RAG 2
- recombination activating genes
*rearrangement is very inefficient, only about 2% make it, rest undergo apoptosis
what structural characteristic (of gene organization) allows for the α chain in pre-T cells to undergo successive arrangements
no diversity segment in the middle
what happens next once a functional α chain is made from rearrangements
the α chain gets sent to the ER and is checked for its interaction w/ β
What occurs at T cell checkpoint 2
interaction b/w new alpha chain and β
- if interaction is successful, the line proliferates
what dictates antigen binding of T cells
the way the alpha and β chains come together
what is Omenn syndrome
RAG deficiency
- patients lack T and B cells
- treated w/ bone marrow transplant otherwise fatal
the T cell development path is marked by _____
gene expression
what does the double positive T cell make
(positive) CD4+, CD8+
what does the double negative T cell make
(negative) CD4-, CD8-
at what stages of T cell development is RAG expression turned on
between the Pro-T and Pre-T stage and as the Pre-T cells becomes the double positive (and so it can make the alpha chain)
what is positive selection of T cells, where does it occur
checks for TCR binding to MHC complexes
determines CD4 vs CD8 expression
*ends w/ single positive T cells
- occurs in cortex of thymus
at what steps of T cell development does Negative selection occur
double positive and single positive step
- “goldilocks”
- can’t bind too weakly to MHC but also can’t bind too strongly (means it recognizes self peptides as antigen and would cause autoimmune response)
After negative selection occurs, the single positive T cell migrates where
to peripheral lymphoid organs (regional lymph nodes, Peyer’s patches, etc)
What occurs during the progenitor T cell phase
- RAG-mediated V-D-J recombination of the β chain is occurring
what occurs during the precursor T cell phase
- The β chain has successfully recombined and is expressed on the cell surface
- RAG-mediated V-J recombination of the α chain is occurring
- Surrogate α chain (pTα) is expressed
What occurs during the double-positive T cell phase
both alpha and beta chains have successfully rearranged and are expressed w/ CD3 + zeta chains as the membrane bound TCR complex
- expression of both CD4 + CD8
- positive and negative selection occurs
what occurs during single positive T cell phase
downregulation of either CD4 or CD8 and final maturation
what occurs during the stage of mature, naive T cell
Cell gets released into circulation as a single positive T cell
what are Naive T cell
mature T cells that have not yet encountered their specific antigen
when do naive T cells encounter their specific antigen? And what happens once they do?
- when it is presented to them by MHC antigen complex
- once this happens they can proliferate and differentiate into effector T cells
how do antigens get delivered to lymphoid tissue
via innate immunity
- inflammation increases blood flow into infected sites, lymph flow increases
Dendritic cells take up antigens and move them into a lymphatic vessel —> lymph node where they settle in T cell areas
how do T cells enter a draining lymph node
- blood vessels (HEV)
- afferent lymphatics from upstream lymph node
what happens to T cells that are not activated by antigens presented by dendritic cells
they exit the lymph node via cortical sinuses and re-enter the blood - a continuous process of recirculation
what cells bring antigens to lymph tissues
dendritic cells
how do naive T cells find their antigen
naive T cells come in from blood stream –> migrate into peripheral lymph tissue where they sample peptides for MHC complexes on dendritic cells
what happens once a T cell finds its antigen
- migration ends
- proliferation and clonal replication occur (‘clonal expansion or priming’)
- gives rise to effector and memory T cells
- after effector differentiation, activated T cells can re-enter the bloodstream
antigens in the blood are carried to the ____ via APCs
spleen
pathogens/antigens on** mucosal surfaces** are carried across the mucosa and into ______ or ______
tonsils or Peyer’s patches
what are the 3 signals for clonal expansion and differentiation?
signal 1 - antigen-specific interaction b/w MHC and TCR
signal 2- co-stimulatory signals b/w B7 and CD28 promote survival and expansion of T cell clones
signal 3 -directing T cells differentiate into effector T cells (IL6, IL12, IL14)
what does it mean for a developing T cell to be double negative
doesn’t express CD4 or CD8
what does it mean for a developing T cell to be double positive
it expresses both CD4 and CD8
Single positive T cell AKA
naive Tcell
successful TCR:MHC binding results in the generation of survival signals and 3 transcription factors…what are they
NFAT
NF-kB
AP-1
the release of survival signals and TFs after successful TCR: MHC binding induces a signaling cascade that results in….
synthesis and secretion of IL2 and the expression of new cell surface receptors and ligands: CD69, IL2Rα, CD40L
what is the role of CD69
retains stimulated T cells in the lymph node
what is S1P
a chemoattractant that is high in the blood and low in tissues (and lymph nodes)
circulating naive T cells have low expression of S1P receptor
what is the purpose of circulating naive T cells having S1P receptors
allows them to respond to the S1P gradient and exit the lymphatic tissue
– T cells that are NOT stimulated by antigen re-express S1PR1
CD69 binds what chemoattractant
S1PR1
causes cells to internalize the complex and turn off S1PR expression
antigen recognition by TCR induces the expression of what IL receptors
IL2 and IL6 via co-stimulatory signals through CD28
what is IL-2 critical for
differentiation of T cells into effector T cells and memory cells
how do drugs that inhibit T cell activation like Cyclosporine work
they target the signal transduction pathways in T cells, inhibiting T cell activation
Cyclosporine: binds cyclophilin, the complex inhibits calcineurin, preventing NF-AT generation
–> w/out NF-AT, transcription of IL2 gene cannot occur
—> IL2 needed for T cell proliferation
what does the ligand CD40L do
binds CD40
- activation of macrophages
- activation of B cells to produce antibodies
What is Hyper IgM syndrome
unable to undergo antibody class switching
what is the role of CTLA-4 inhibitory receptor
- binds B7 on APC to limit T-cell proliferation
- blocks CD28 signaling (the 2nd signal in T cell activation)
the prolonged maintenance of memory T cells is dependent on what
Cytokines
what cells are especially important in defense against viral pathogens
CD8 T cells
what are 2 main granules cytotoxic T cells contain
- perforin = pore forming protein
- granzymes = serine proteases activate caspases in host cells to trigger apoptosis
TGF-β stimulates what helper cell
T regulatory cells
IL-6 stimulates what helper cells
TFH
TGF-β and IL-6 stimulate what helper cells
TH17
IL-12 and IFNγ stimulate what helper cells
TH1 cells
IL-4 stimulates what helper cells
TH2
TH1 cells do what
control bacteria that can grow in macrophages
express IL-2 and IFNγ
TH2 cells do what
control parasitic infection
express IL4, IL5, IL13 that promote mast cells, eosinophils and B cell class switching to make IgE
what do TH17 cells do
stimulate neutrophil response to extracellular bacteria and fungi
Make IL 17 & IL 22
what do TFH cels do
stimulate antibody production from B cells, including class switching and affinity maturation
what drives TH2 cell differentiation
IL4 in response to helminths and allergens
- mast cells, when stimulated by helminths, secrete IL4
what type of class switching does IL4 stimulate
B cells to IgE
what does IL5 do
activate eosinophils
what do IL4 and IL13 do
stimulate increased mucus secretion
what drives TH17 cell differentation
pro-inflammatory cytokines and TGF-β
What does IL17 stimulate
recruitment of neutrophils and production of anti-microbial peptides
what does IL22 do
promotes epithelial integrity, antimicrobial peptides and mucins
what drives TH17 cell differentiation
proinflammatory cytokines + TGF-β
what does TH17 secrete
IL-17 : stimulates recruitment of neutrophils and production of anti-microbial peptides
IL-22: promotes epithelial integrity, antimicrobial peptides, and mucins
