T cells/T cell receptors and Antigen Presenting Cells Flashcards
What are the three cells of innate immunity?
Phgocytes, NK cells, Dendritic Cells
What are the two types of dendritic cells?
Antigen presenting (mDC) and Interferon-producing (pDC)
Cells of innate immunity are also cells of
Adaptive immunity
Have a variety of functions including phagocytosis, secretion of cytokines and antigen presentation
Dendritic Cells (DCs)
Collect proteins, some of which come from disease causing pathogens
Antigen Presenting Cells (APCs)
Break down the proteins into peptides (short protein fragments 8-15 amino acids)
APCs
APCs show these peptide fragments to
T cells
Initiate the adaptive immune response
APCs
Naïve T cells have not been exposed to
Antigen
Do little/nothing to directly clear infections
Naïve T cells
Produce effector molecules like cytokines (IL-4, IFN-γ)
Effector T cells
Long lived, antigen specific cells that respond very quickly if reexposed to same antigen; rapid production of effector molecules/functions
Memory T cells
Lymphocyte clones mature in generative lymphoid organs in the absence of
Antigens
Clones of mature lymphocytes specific for diverse antigens enter
Lymphoid tissues
Antigen-specific clones are then activted by
Antigens
The result is an antigen-specific
Immune response
Effector T cells and antibodies persist for weeks after exposure to antigen. This is called
Protective immunity
Innate immune system signaling (i.e. TLRs) activates
-Causing maturation
DCs
Must receive 2 signals to be fully activated
T cells
Costimulatory molecules are upregulated on
-following signals from the innate immune system
APCs
Binding of T-cell receptor (TCR) to the antigen-HLA complex on the dendritic cell (DC) delivers a signal (signal 1) that can induce
Activation and expansion of T cells
The costimulatory signal (signal 2) is given by binding of
CD28 to B7 molecules
Lack of costimulation inhibits
T cell responses
Lack of Costimulation Inhibits T cell Responses. This is one reason that
Tumors are hard to clear
Malignant tumor cells express Tumor Restricted Antigen (TRA) but no costimulatory molecules. As a result, CD8 T cells specific for the TRA can not be
Activated
Upregulated on T cells after T cell is activated
CTLA-4
Also binds to B-7, but its function is to shut down the T cell response
CTLA-4
Cross-linking of CD28 delivers the co-stimulatory signal during activation of naive T cells and induces the expression of
CTLA-4 (CD152)
CTLA-4 is upregulated soon after T cell activation. It is essential for
Shutting down T cell responses
Mice without CTLA-4 die days after birth as a result of massive T cell infiltration of major
Organs
Therapeutic costimulatory blockades are used as a strategy to block the function of autoreactive T cells to prevent
Autoimmunity
To do this, we inject soluble CTLA-4 (CTLA-4-Ig) binds to B7 and prevents T cell from receiving signal 2 from
APC
-as a result, T cell becomes anergic
We can enhance anti-tumor T cells by blocking the function of
-patient will often experience autoimmunity as well
CTLA-4
What is the CTLA-4 blocker produced by Bristol-Myers Squibb?
Ipilimumab (Yervoy)
In the early signalling events in T cell activation, TCR complex and coreceptors cluster within membrane lipid rafts upon
Antigen recognition
Then, Lymphocyte specific protein tyrosine motif (LCK) phosphorylates tyrosines in
ITAM
Next, ZAP-70 binds to phosphotyrosines and phosphorylates adaptor proteins including
Linker for Activation of T cells (LAT)
Recognizes complex of viral peptide with MHC class I and kills the infected cell
Cytotoxic (CD8) T cells
What are the two typed of CD4 T cells?
TH1 and Helper T cells
Recognizes complexes of bacterial peptides with MHC class II and activated macrophages
TH1
Recognizes complexes of antigenic peptide with MHC class II and activates B cells
Helper T cells
Functions to stimulate IgG production
TH1 cells
Stimulates the production of IgE
TH2 cells
Functions in classical macrophage activation and enhanced microbial killing
TH1
two of the main functions of TH2 are
Antibody production and mast cell degranulation
Also functions in intestinal mucus secretion and peristalsis and eosinophil activation
TH2 cells
TH2 cells can also function in as an alternative for macrophage activation which results in
Enhanced fibrosis/tissue repair
Functions in inflammation and to generate anti-microbial peptides. The also increase barrier function
TH17 cells
Inhibit T cell activation and T cell effector functions
Regulatory (Tregs) T cells
What are the 4 mechanisms of Treg function?
- ) DC targeting
- ) Inhibitory cytokines
- ) Cytolysis
- ) Metabolic disruption
Peptides from pathogens are presented to T cells in the context of
MHC
What happens if the pathogen changes such that its peptides cannot be presented by MHC?
No immune response will occur
Simian Immunodeficiency Virus (SIV) escapes CD8 T cells by mutating amino acids necessary for binding to
MHC class I
Cytotoxic T-lymphocyte (CTL) responses to human immunodeficiency virus arise early after
Infection
Human immunodeficiency virus may evade the CTL response by accumulating amino-acid replacements within
CTL epitopes
TCRs must bind to your MHC molecules, but not bind too strong (high avidity) such that the T cell is activated and causes
Autoimmunity
Selects the useful T cells, eliminates the dangerous T cells, and ignores the rest
T cell development
Picks out the T cells with useful TCRs
Positive selection
What percentage of thymocytes fail positive selection and die?
95%
Eliminates the T cells with dangerous TCRs
Negative selection
What percentage of positively selected thymocytes are subsequently killed by negative selection
70%
T cell recognition of self peptide-MHC is necessary for both
Positive and Negative Selection
Expression of MHC in the thymus is required for
Positive selection
T cell subsets develop in the
Thymus
What are the 4 T cell subsets that develop in the thymus?
- ) CD4+ T cells
- ) CD8+ T cells
- ) Treg T cells
- ) NKT cells
Making sure your immune system does not attack your own body
Immunological Tolerance
What are the two types of immunological tolerance?
Central tolerance and peripheral tolerance
Occurs in the thymus (T cells) and bone marrow (B cells)
Central Tolerance
The affinity of the TCR on developing thymocytes determines if the cell is
Positively or negatively selected
Thymic function decreases with
Age
In the aged thymus, the perivascular space (P) is increased in size and the thymopoietic cortex (C) and medulla (M) are significantly
Constricted
The TCR repertoire of the naive and memory CD4+ T cell compartments changes with
Age
A cure for leukemia and other cancers, and a fantastic tool to study the immune system *The bone marrow chimeric mouse
Bone marrow transplant
Killed by chemotherapy and radiation
Hematopoetic Cells
Not killed by chemotherapy and radiation
Epithelial/stromal cells
After a bone marrow transplant, immune cells will have genotype of the donor, while the epithelial/stromal cells will have the genotype of the
Host
Cell surface marker on all hematopoietic cells
CD45
What are the 5 steps of a bone marrow transplant to cure cancer?
- ) Collection
- ) Processing
- ) Cryopreservation
- ) Chemotherapy
- ) Reinfusion
Death after a bone marrow transplant is often caused by infection because T cells do not
Reconstitute
Multi-potent cells are directed into the
T cell lineage
RAG1/2 (Recombination Activating Genes 1 /2 are expressed and mediate
V(D)J recombination of the TCR loci
Thymocytes undergo positive selection and then undergo
Negative selection
Then, multiple lineages are defined such as
CD4, CD8, Treg, etc
The selected thymocytes have TCRs that are
MHC restricted
Experimental results showed that T cells cannot respond to cells from different strains of mice infected with the same
Same virus