Flashcards in Lecture 7 (Dustin) - T cells Deck (41):
Where do T cells originate and where do they mature?
Originate in the bone marrow like B cells, but travel to the thymus for maturation
(remember bone marrow and thymus are primary lymphoid organs)
What 2 major events take place in the thymus for T cell maturation?
Positive and negative selection
Where do mature but inactive T cells reside? Where do the activated ones go?
Mature T cells live in the peripheral/secondary lymphoid organs (spleen, lymph follicles)
When activated, they travel to sites of infection
What are immature T cells called?
What do they gain when they are matured?
Upon maturation, they gain a functioning T cell receptor that is specific for an antigenic determinant
Within the thymus, thymocytes travel from the ____ to the ____ as they undergo the maturation process
travel from the cortex to the medulla
(cortex is more "cell rich" than medulla bc many thymocytes die in the process)
What are the two classes of T cell receptors?
1. alpha beta T cell receptor: has alpha and beta subunit
2. gamma delta T cell receptor: has gamma and delta subunit.
Thymocytes begin lacking CD4 or CD8, what is this called? How many phases do they have in this stage, and what is decided during this period?
They're called "double negative" or DN.
There are 4 phases: DN1-DN4. Various surface proteins exist on them in these stages
During this phase, gene rearrangement of the receptor chain occurs, and it is decided if they will gain alpha-beta (and need additional maturation steps) or gamma-delta receptors (that can leave thymus without further receptor selection).
What process takes place for TCR diversity, and where does it occur?
VDJ recombination/gene rearrangment (same as with immunoglobulins), and it takes place in the thymus cortex
What happens to alpha beta T cells when they first transition from the double negative phase?
First they become double positive (contain both CD4 and CD8). A cortical epithelial cell will then help them to differentiate into only "single positive" CD8+ or CD4+
What do TCR recognize?
How does it differ between cytotoxic vs helper T cells?
Recognize an MHC complex + a peptide fragment
Tc recognize MHC I, Th recognize MHC II
What region of the TCR does the recognition?
CDR: Complementarity Determining Regions
What is it important for T cell receptors to be able to detect and not detect?
Should be able to detect self MHC molecules, but not detect self antigens (to prevent autoimmune reaction)
What is the aim of positive selection?
Recognize self MHC + peptide. If the TCR has only weak or no binding, then it's useless and so it undergoes apoptosis.
What type of cells facilitate positive selection? How does this work?
Cortical epithelial cells. They express both MHC I and MHC II. Either CD4 will bond to MHC II, or CD8 will bond to MHC I, and whichever CD was not bound will later be eliminated
Which type of cells carry out negative selection? How does this work?
Medullary epithelial cells. They have "promiscuous gene expression" - expressing many of the genes (5-10%) that will be encountered throughout the body. With these, they safely test the TCR to see if it will be reactive against self antigens.
What controls the expression of self peptides by thymic medullary cells?
AIRE: AutoImmune REgulator
How many T cells survive positive selection?
How many survive negative selection?
45% survive positive selection (are able to recognize MHC's correctly)
Only 5% survive negative selection (and don't recognize self antigens)
What type of T cells are they when they leave the thymus?
Single Positive naive/virgin T cells: have not yet encountered antigens, and when they do, they'll become effector T cells
How many types of antigens can one TCR bind?
Only one, but there are many T cells and they have a huge diversity of receptors. So, as a whole, many antigens can still be detected.
Dendritic cells travel from the _____ to ____ in order to present antigens to naive T cells
travel from the periphery to the lymph node "deep cortex" or paracortex to find naive T cells that have the right TCR for their antigen. (alternatively, in the spleen the T cell-rich area is the PALS)
When a naive CD4+ T cell meets an APC with a matching antigen, what happens?
1. The TCR and CD4 together help bind the MHC II + peptide complex.
2. Positive Costimulation: B7 (aka CD80) on the APC binds to CD28 of the T cell
3. Those two things combine to stimulate the CD3 ITAM motif to begin activity, leading to numerous signaling pathways and transcription factors that lead the T cell to synthesize IL-2
What interleukin is key to early Th cell activation when it encounters an APC, and how does it work?
IL-2 (we should be calling it "T cell growth factor") is synthesized by the T cell, released out and then it has autocrine self-stimulation to signal cell division, producing many clones
What occurs in order to get the T cell to stop proliferating, about 24 hours after it has been activated?
Negative Costimulation: the T cells start producing CTLA4, PD1, and ICOS on their surface. These connect to the APC's B7 surface receptor, and will stop T cell proliferation due to their ITIM motif ("i" for inhibitory).
What type of (mature) T cells are negative for both CD4 and CD8?
gamma delta T's and natural killer T's
What are the 3 types of T cells that can be either CD4 or CD8 positive?
Helper (CD4+), Regulatory (CD4+), or Cytotoxic (CD8+)
What 3 things do cytotoxic T cells express to help them target viral-infected or tumor cells?
3. Fas Ligand
How do cytotoxic T cells kill infected cells?
The TCR and CD8 bind MHC I + peptide. This will trigger the cell to release granules with perforins + granzyme. Perforins penetrate the cell membrane, while granzymes enter and trigger apoptosis.
Fas Ligand binds to the cell's Fas (death receptor) and also induces apoptosis
What would happen if a TCR was able to recognize a self peptide?
It would kill destroy it, meaning the Tc is autoreactive
What helps determine if a naive Th cell will become a Th1 or Th2 cell?
If IL-12 is present, then the Th will become Th1.
What two cytokines are secreted by Treg cells?
IL-10 and TGF beta
What types of cells to Th1 cells stimulate? What major cytokine is used?
NK cells and macrophages
use IFN gamma
What type of cells to Th2 cells stimulate? What is the major cytokine?
B cells (most importantly), also eosinophils and basophils
What type of cells to Th17 cells stimulate? What is the major cytokine?
IL-17 used (at least it matches the Th cell type...)
What effect to Th1 and Th2 have on each other?
They inhibit each other, again some sort of homeostatic balance is necessary and they have competing cytokines
Where do Th1 cells go after they're activated?
They go to the periphery and stimulate macrophages to effectively clear bacteria, also stimulate Tc cells and NK cells
How do natural Treg cells develop?
Start in the CD4+ path in the thymus, but they show only weak avidity/binding to MHC complexes. They are allowed to survive and go on into the periphery to just be natTreg cells
What are the cytokines of Treg cells (again) and what do they do?
TGF-beta and IL-10
They stop expression of co-stimulatory molecules on both APC's and Th cells, thereby regulating the immune response and generating "immunotolerance." These Treg cells must recognize self peptides in order to create these cytokines.
Where do gamma delta T cells go?
They travel to areas that line the body, such as mucosal and cutaneous tissues, as part of the first line defense.
They do not depend on MHC's for antigen recognition
What can gamma delta T cells recognize?
Nothing to do with MHC's, but they are thought to interact with unprocessed non-protein antigens
What happens if a gamma delta T recognizes a pattern of a damaged keratinocyte?
Activates the gamma delta T, causing it to both eliminate the damaged cell (cytotoxic effect) and influence surrounding cells (like a Th cell). They even help create repair molecules (FGF-7 and IGF-1)