T Cells/TCR Flashcards
What initiates the adaptive immune response?
APCs
What are 2 things a naive T cell can differentiate into after activation
Effector T cells or Memory T cell
What do effector T cells do?
Produce Cytokines (like IL-4 and IFN-gamma)
What do memory T cells do?
Long lived (weeks/months/years); “protective immunity”: antigen specific; respond quickly if re-exposed to same antigen–> rapid production of effector molecules/fxns
Clonal Selection Hypothesis
1) Lymphocyte clones mature in generative lymphoid organs in absence of antigens.
2) Clones of mature lymphocytes specific for diverse antigens enter lymphoid tissues (e.g. spleen and lymph nodes)
3) Antigen-specific clones are activated (“selected”) by antigens.
4) Antigen-specific immune responses occur. (Anti-X antibody)
What is “protective immunity”?
effector T cells and antibodies persist for weeks after exposure to antigen
What is “immunological memory”?
second exposure to same antigen that produces a much faster resposne
How are dendritic cells activated?
Innate immune system signaling (Toll-like Receptors) –> activate DCs –> cause maturation
How are DC antigens presents?
0) immature DC is in epidermis (Langerhans cell)
1) antigen is captured by DC and then DC is activated/matured
2) DC migrates via lymphatics
3) in the lymph nodes, the mature dendritic cell presents the antigen to the native T cell
What to T cell Receptors recognize?
The MHC complex WITH the peptide. (need to see both)
What two signals are necessary to fully activate a T cell (co-stimulation)?
1) binding of TCR to antigen-HLA(MHC) complex on dendritic cell
2) binding of CD28 (T cell) to B7 (expressed by DC) molecules
**Also causes up-regulation of B7 = fundamental for activiation
What happens if a naive T cell binds to an antigen (on TCR) but CD28 can’t find a B7?
No response or anergy (tolerance)!
It’s co-stimulator deficient so it senses that what it is binding to is NOT not-self (eg: it could be self) –> therefore needs to shut down that T cell (for days/weeks/always) so you don’t have an autoimmune response.
What is the role of IL-12
Co-stimulatory for T cell proliferation (but can’t surpass need for B7 interaction)
What is the normal mechanism of T cell response?
DC’s B7 and MHC+antigen bind to CD28 and TCR (respectively) to activate effector and memory T cells
Why are tumors hard to clear?
May be presenting lots of MHC but are recognized as “self” (no B7 so corresponding T cells are lost)
Native CD8 T cells specific for TRA (tumor restricted antigen) cannot be activated by the tumor cells and may be rendered anergic
( lack co-stimulation, which inhibits T cell responses –> tumor grows)
What is a cytokine storm?
T cell response not turned off
(eg. sepsis; toxic shock syndrome
How are T cell responses turned off?
CTLA-4 is expressed (after cross-linking of CD28)
1) CTLA-4 is up-regulated on T cells after T cell is activated.
2) CTLA-4 binds B7 more avidly than does CD28 and delivers inhibitory signals to activated T cells (to shut down T cell response)
Theraputic Costimulatory Blokade
strategy to block the function of autoreactive T cells (prevent autoimmunity)
Injected soluble CTLA-4 (CTLA-4-Ig) binds to B7 and prevents T cell from receiving signal 2 from APC
Thus, T cell becomes anergic
What is the result of monoclonal Ab injections (YERVOY) regarding tumor immunity?
block the function of CTLA-4 (prevent interaction of CTLA-4 and B7 interaction), thus preventing the cell from receiving the “shut down” signal –> T cells (including anti-tumor T cells) will say active and can clear the tumor
Side effects: some type of autoimmunity, usually GI
VERY SUCCESSFUL!
T-cell Receptor (TCR)
NB: all T-cells have CD3!
alpha and beta subunits (larger extracellular part); connected by disulfide bond
other zeta dimer part that extends more into cyto (has ITAMS in cyto)
ITAM
immunoreceptor tyrosine-based activation motif
What are the “early” signaling events in T cell activation?
1) TCR complex and coreceptors cluster with in membrane lipid rafts upon antigen recognition –>
2) LCK phosphorylates tyrosines in ITAMs
3) ZAP-70 binds to phosphotyrosines and phosphorylates adaptor proteins, including LAT
LCK
lymphocyte specific protein tyrosine kinase
ZAP-70
zeta chain associated protein
binds to phosphotyrosines and phosphorylates adaptor proteins, including LAT
LAT
Linker for Activation of T cells
Adhesion molecules
- 2 examples of ligands?
- how activated?
allow T cells to stick and get activated
ICAM-1: antigen presenting cells; endothelium (interacts with LFA-1)
VAM-1: endothelium (interacts with VLA-4)
CD8 T cells
cytotoxic T cell recognizes complex of viral peptide with MHC class I and kills infected cells
What are 2 types of CD4 T cells?
Th1: recognizes complex of bacterial peptide with MHC class II and activates macrophage
Helper T cell: recognizes complex of antigenic peptide with MHC class II and activates b cell
Natural Killer T Cells
subset of T cells (48 min)
Subsets of T cells and cytokines
(Figure 9-13) Slide 31
What are the signature cytokines of a TH1 cell?
Immune Reactions?
Host Defense?
Role in Disease?
Cytokine: IFN-gamma
Immune Reactions? CLASSIC Macrophage activation (enhanced microbial killing); IgG production
Host Defense? intracellular microbes
Role in Disease? autoimmune diseases; tissue damage associated with chronic infections
What are the signature cytokines of a TH2 cell?
Immune Reactions?
Host Defense?
Role in Disease?
Cytokines: IFN-4, 5, 13
Immune Reactions? Mast cell, eosinophil activation, IgE production; “alternative” macrophage activation
Host Defense? helminthic parasites
Role in Disease? allergic diseases
What are the signature cytokines of a TH17 cell?
Immune Reactions?
Host Defense?
Role in Disease?
Cytokine: IFN-17A, 17F, 22
Immune Reactions? neutrophilic, monocytic inflammation
Host Defense? extracellular bacteria; fungi
Role in Disease? organ specific autoimmunity
