Lecture 7 (Dustin) - T cells

Question 1

Where do T cells originate and where do they mature?

Answer 1

Originate in the bone marrow like B cells, but travel to the thymus for maturation

(remember bone marrow and thymus are primary lymphoid organs)

Question 2

What 2 major events take place in the thymus for T cell maturation?

Answer 2

Positive and negative selection

Question 3

Where do mature but inactive T cells reside? Where do the activated ones go?

Answer 3

Mature T cells live in the peripheral/secondary lymphoid organs (spleen, lymph follicles)

When activated, they travel to sites of infection

Question 4

What are immature T cells called?

What do they gain when they are matured?

Answer 4

Thymocytes

Upon maturation, they gain a functioning T cell receptor that is specific for an antigenic determinant

Question 5

Within the thymus, thymocytes travel from the ____ to the ____ as they undergo the maturation process

Answer 5

travel from the cortex to the medulla

cortex is more “cell rich” than medulla bc many thymocytes die in the process

Question 6

What are the two classes of T cell receptors?

Answer 6

1. alpha beta T cell receptor: has alpha and beta subunit

2. gamma delta T cell receptor: has gamma and delta subunit.

Question 7

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?

Answer 7

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).

Question 8

What process takes place for TCR diversity, and where does it occur?

Answer 8

VDJ recombination/gene rearrangment (same as with immunoglobulins), and it takes place in the thymus cortex

Question 9

What happens to alpha beta T cells when they first transition from the double negative phase?

Answer 9

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+

Question 10

What do TCR recognize?

How does it differ between cytotoxic vs helper T cells?

Answer 10

Recognize an MHC complex + a peptide fragment

Tc recognize MHC I, Th recognize MHC II

Question 11

What region of the TCR does the recognition?

Answer 11

CDR: Complementarity Determining Regions

Question 12

What is it important for T cell receptors to be able to detect and not detect?

Answer 12

Should be able to detect self MHC molecules, but not detect self antigens (to prevent autoimmune reaction)

Question 13

What is the aim of positive selection?

Answer 13

Recognize self MHC + peptide. If the TCR has only weak or no binding, then it’s useless and so it undergoes apoptosis.

Question 14

What type of cells facilitate positive selection? How does this work?

Answer 14

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

Question 15

Which type of cells carry out negative selection? How does this work?

Answer 15

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.

Question 16

What controls the expression of self peptides by thymic medullary cells?

Answer 16

AIRE: AutoImmune REgulator

Question 17

How many T cells survive positive selection?

How many survive negative selection?

Answer 17

45% survive positive selection (are able to recognize MHC’s correctly)

Only 5% survive negative selection (and don’t recognize self antigens)

Question 18

What type of T cells are they when they leave the thymus?

Answer 18

Single Positive naive/virgin T cells: have not yet encountered antigens, and when they do, they’ll become effector T cells

Question 19

How many types of antigens can one TCR bind?

Answer 19

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.

Question 20

Dendritic cells travel from the _____ to ____ in order to present antigens to naive T cells

Answer 20

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)

Question 21

When a naive CD4+ T cell meets an APC with a matching antigen, what happens?

Answer 21

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

Question 22

What interleukin is key to early Th cell activation when it encounters an APC, and how does it work?

Answer 22

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

Question 23

What occurs in order to get the T cell to stop proliferating, about 24 hours after it has been activated?

Answer 23

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).

Question 24

What type of (mature) T cells are negative for both CD4 and CD8?

Answer 24

gamma delta T’s and natural killer T’s

Question 25

What are the 3 types of T cells that can be either CD4 or CD8 positive?

Answer 25

Helper (CD4+), Regulatory (CD4+), or Cytotoxic (CD8+)

Question 26

What 3 things do cytotoxic T cells express to help them target viral-infected or tumor cells?

Answer 26

1. TCR
2. CD8
3. Fas Ligand

Question 27

How do cytotoxic T cells kill infected cells?

Answer 27

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

Question 28

What would happen if a TCR was able to recognize a self peptide?

Answer 28

It would kill destroy it, meaning the Tc is autoreactive

Question 29

What helps determine if a naive Th cell will become a Th1 or Th2 cell?

Answer 29

If IL-12 is present, then the Th will become Th1.

Question 30

What two cytokines are secreted by Treg cells?

Answer 30

IL-10 and TGF beta

Question 31

What types of cells to Th1 cells stimulate? What major cytokine is used?

Answer 31

NK cells and macrophages

use IFN gamma

Question 32

What type of cells to Th2 cells stimulate? What is the major cytokine?

Answer 32

B cells (most importantly), also eosinophils and basophils

Use IL-4

Question 33

What type of cells to Th17 cells stimulate? What is the major cytokine?

Answer 33

Inflammatory, PMNs

IL-17 used (at least it matches the Th cell type…)

Question 34

What effect to Th1 and Th2 have on each other?

Answer 34

They inhibit each other, again some sort of homeostatic balance is necessary and they have competing cytokines

Question 35

Where do Th1 cells go after they’re activated?

Answer 35

They go to the periphery and stimulate macrophages to effectively clear bacteria, also stimulate Tc cells and NK cells

Question 36

How do natural Treg cells develop?

Answer 36

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

Question 37

What are the cytokines of Treg cells (again) and what do they do?

Answer 37

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.

Question 38

Where do gamma delta T cells go?

Answer 38

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

Question 39

What can gamma delta T cells recognize?

Answer 39

Nothing to do with MHC’s, but they are thought to interact with unprocessed non-protein antigens

Question 40

What happens if a gamma delta T recognizes a pattern of a damaged keratinocyte?

Answer 40

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)

Question 41

What is responsible for the limited diversity of the TCR of natural killer cells?

Answer 41

They have alpha beta receptors, but the alpha chain is the same on all NK T cells