T cell activation (cell-mediated immunity I)

Question 1

T-cell development can be grouped into 4 sequential steps.

Briefly describe them.

Answer 1

1&2. T-cell progenitors develop in the bone marrow and migrate to the thymus where the cells complete their development by rearranging their antigen-receptor genes and undergoing repertoire selection.

3. Mature T cells encounter foreign antigens in the peripheral lymphoid organs and become activated.
4. Activated T cells proliferate and eliminate infection in sites of infection.

Question 2

Briefly describe how peripheral lymphoid organs promote interactions between lymphocytes and antigens.

Answer 2

The organization of each organ is similar - they have DISTINC T cells and B cell zones, enhancing the interaction between circulating T cells and B cells with APCs and free antigens, respectively.

Question 3

The lymph node contains distinct B cell zones and T cell zones.

Dendritic cells loaded with antigen enter the lymph node via _________ lymphatics to the ________ sinus where they then migrate to the __ cell zone.

In this zone, T cells can interact by chance with dendritic cells presenting antigen that matches the specificity of their TCRs and initiate _______ responses.

T cells and B cells enter the lymph node via __________ to T cell zones, and B cells migrate to B cell zones.

Answer 3

afferent; subcapsular; T

adaptive

high endothelial venules (HEVs)

Question 4

Lymph node stromal cells and high endothelial valves (HEVs) secrete the chemokine ________.

Dendritic cells express a receptor for ________ and _______ into the developing lymph node.

In the lymph node, dendritic cells secrete _______, which attracts __ cells to the lymph node.

Simultaneously, B cells are initially attracted into the developing lymph node by the same chemokines.

B cells induce the differentiation of ______ _____ cells which secrete _____ to attract more B cells, creating B cell zones.

Answer 4

CCL21

CCL21; migrate

CCL19; T

follicular dendritic cells; CXCL13

*chemokines drive cell migration, causing T cell zones and B cell zones to be generated.

Question 5

(T/F) Follicular dendritic cells are the same as antigen-presenting dendritic cells.

Answer 5

False!

FDCs are unrelated to the dendritic cells found in the T cells. These are not leukocytes, are not phagocytic and do not express MHC II.

Question 6

(T/F) Dendritic cells enter lymph nodes through blood streams only.

Answer 6

False!

During the development of the lymph nodes, it is unclear if dendritic cells enter the bloodstream or the lymphatics. Later in life, dendritic cells enter via the lymphatics.

Question 7

1) How do T cells enter the lymph node cortex?

2) What happens to the naive T cells that are not activated by the antigens on the dendritic cells?

3) What happens to naive T cells that encounter their specific antigen?

Answer 7

1) T cells enter lymph node cortex from the blood via HIGH ENDOTHELIAL VENULES (HEVs).

2) Naive T cells continuously circulate from the blood into lymph nodes. In the lymph node, naive T cells sample peptide:MHS complexes on dendritic cells. T cells that do not encounter their antigen leave the lymph node and return to the bloodstream.

3) Naive T cells that encounter their specific antigen REMAIN in the T cell zone and PROLIFERATE, DIFFERENTIATE into EFFECTOR CELLS. They then EXIT THE LYMPH NODE and enter circulation where they migrate to sites of infection.

Some effector T cells migrate to B cell zones to help with B cell activation.

Question 8

What happens when a naive T cell encounters its antigen? Why?

Answer 8

When a naive T cell encounters its antigen, it is rapidly TRAPPED and TRANSIENTLY DETAINED within the lymph node.

A very small portion of naive T cells can recognize a particular antigen. As such, adaptive immunity depends on the activation, proliferation and differentiation of these rare T cells. This is MEDIATED BY THE TEMPORARY DETAINMENT of antigen-specific T cells within the lymph node.

This process is very efficient – naive T cells can be trapped by its specific antigen within 2 days following infection. Roughly 5 days after infection, the now-activated effector T cells leave the lymph node in large numbers.

Question 9

1) What are S1P and S1PR1? What does S1PR1 signalling promote?

2) How do naive T cells that encounter antigens get trapped and transiently detained within the lymph node?

3) How do effector T cells eventually move out of the lymph node?

Answer 9

1) S1P is a signalling molecule that binds to S1PR1, which is expressed on T cells. There are less and less S1P as you enter the lymph node. T cells that express S1PR1 are attracted to S1P, causing them to egress out of the lymph node.

2) The S1PR1 molecule of a naive T cell that encounters its antigen is DOWNREGULATED, causing it to have little attraction to move outside of the lymph node. This causes the retention which allows for proliferation.

3) After a certain amount of time, the S1PR1 molecule is UP-REGULATED, causing effector cells to want to migrate outside of the lymph node.

Question 10

What does priming of naive T cells mean?

Answer 10

The ACTIVATION and DIFFERENTIATION of naive T cells in the peripheral lymphoid tissues is called PRIMING.

The molecular signals for priming are different than the signals for effector/memory T cells.

Question 11

Priming of naive CD8+ T cells generates cytotoxic T cells that can directly kill _______-______ cells whereas priming of naive CD4+ T cells leads to the generation of a range of CD4+ T cell subtypes each of which involves the secretion of specific _______ that enhance/modulate the ______ response.

Answer 11

pathogen-infected

cytokines; defense

Question 12

The priming of naive T cells by pathogen-activated dendritic cells (APCs) can be divided into three phases.

What are the three phases?

Answer 12

1) Recognition (stimulation of naive T cells)

2) Proliferation/differentiation

3) Effector function (active effector T cells kill virus-infected target cells or secrete cytokines to enhance defence responses)

Question 13

(T/F) Il-2 is a key cytokine for survival.

Answer 13

True!

Question 14

1) Cell _______ molecules mediate the initial interaction of naive T cells with antigen-presenting cells.

2) Naive T cells transiently interact with APCs within the lymph node. Why is this low-affinity interaction important?

3) What happens once the naive T cell recognizes its peptide:MHC ligand? How long can this interaction persist for?

Answer 14

1) adhesion

2) It is important because it allows the T cell enough time to search for its specific peptide:MHC ligand.

3) Once the naive T cell recognizes its peptide:MHC ligand, signalling through the TCR triggers a conformational change within LFA-1 (on T cell) that significantly increases its affinity for ICAM-1 and ICAM-2 (on APCs).

This interaction can persist for long periods (i.e. hours, days) whereby the T cell becomes activated, proliferates & differentiates into effector T cells.

Question 15

What are the three signals required for the activation of naive T cells by APCs?

Answer 15

Signal 1 is generated by the interaction of the
peptide:MHC complex on the APC with the
TCR/co-receptor complex on the naive T cell. This
interaction contributes to T cell ACTIVATION.

Signal 2 is generated by the interaction of COSTIMULATORY MOLECULES (B7-1, B7-2) on APCs with co-stimulatory receptors (CD28) on T cells. This
interaction contributes to the SURVIVAL and
PROLIFERATION of the T cells.

Signal 3 is generated by CYTOKINES that direct T cell
differentiation into distinct EFFECTOR T cell subsets. These cytokines are secreted by APCs and are particular to certain infections.

Question 16

1) When are B7 co-stimulatory molecules upregulated on an APC cell?

2) Compare and contrast B7-1 and B7-2.

3) Briefly describe the structure and function of CD28.

Answer 16

1) B7 co-stimulatory molecules are upregulated on an APC cell following TLR (toll-like receptor) signalling.

2) B7-1 and B7-2 are structurally similar INTEGRAL membrane proteins; temporal pattern of expression differs.

3) CD28 is a DISULFIDE-LINKED HOMODIMER that contains signalling motifs within its cytoplasmic domains. When it binds to B7 molecules, it recruits signalling factors during T-cell activation.

Question 17

Many receptors homologous to CD28 and ligands homologous to B7 have been identified.

They can either activate or inhibit T cell responses. Expression of these receptors may be constitutive or induced in response to signalling events.

Give some examples.

Answer 17

1) CD28: CONSTITUTIVE and activates T cell responses.

2) CTLA-4: INDUCIBLE and inhibits activation of T cells.

3) PD-1: INDUCIBLE and inhibits activation of T cells.

*2 and 3 are induced after activation of T cells.

Question 18

CTLA-4 is initially present within ________ membranes. Following T cell activation, CTLA-4 is transported to the T cell _______.

CTLA-4 functions by blocking _______ of B7 to CD28, thereby reducing CD28-dependent signalling.

Answer 18

intracellular; surface

binding

*CTLA-4 thereby serves to regulate the proliferative phase of the activated T cell response (i.e. restricts IL-2 production).

Question 19

How does PD-1 inhibit the activation of T cells?

Answer 19

Some inhibitory molecules such as PD-1 contain ITIMs.

Phosphorylated ITIMs recruit protein or lipid phosphatases which function to counteract ITAM-based TCR signalling events.

Question 20

Dendritic cells are activated by _______.

______ recognition promotes TLR signalling which not
only enhances _______ ________ but also induces
expression of _____ (allows for migration to lymph
node) and promotes _________ of co-stimulatory
molecules (B7) and MHC molecules.

Answer 20

PAMPs.

PAMP; antigen processing; CCR7; upregulation

Question 21

Which one of the statements is true?

1) Activated dendritic cells (by MAMPs) are still phagocytic while also functioning very effectively as an APC to activate naive T cells within the lymph node.

2) Dendritic cells serve as a bridge for adaptive and innate cell responses.

Answer 21

2!

For 1) Activated dendritic cells (by MAMPs) are NO LONGER phagocytic BUT can function very effectively as an APC to activate naive T cells within the lymph node.

Question 22

What is the role of T cell co-stimulatory molecules (especially CD28) during T cell activation?

Give an example.

Answer 22

T cell costimulatory molecules enhance TCR signalling, leading to amplification of downstream responses mediated by the TCR for the activation of T cells.

For example, the integration of signalling from the TCR and CD28 co-stimulatory molecule promotes the binding of AP-1, NFAT, and NFkb TFs to the promoter of genes such as Il-2.

Question 23

In addition to the B7 co-stimulatory molecules and the CD28 receptor, other co-stimulatory molecules are also involved in T cell activation.

What is an example of one of these additional co-stimulatory molecules?

Answer 23

TCR and co-stimulatory interactions between the T cell and APC cause signals to be transmitted IN BOTH DIRECTIONS (both the T cell and the APC)!

These signals cause the APC to express the additional co-stimulatory receptor CD40 and the T cells to express the additional co-stimulatory molecule CD40 ligand (CD40L).

CD40-CD40L signalling promotes increased B7 EXPRESSION on the APC, thereby stimulating further T cell proliferation.

Question 24

T cell activation promotes ______ and ______ of effector T cells.

Answer 24

proliferation; differentiation

*T cell proliferation requires the expression of Il-2 and high affinity IL-2 receptor.

Question 25

What is the difference in the IL-2 receptor components between a naive T cell and an activated T cell?

What kind of affinity to the IL-2 molecule do the two scenarios create?

Answer 25

Naive T cell: b and y chains expressed constitutively on the T cell surface. this complex binds IL-2 with MODERATE affinity.

Activated T cell: activation promotes EXPRESSION OF ALPHA CHAIN to form the HIGH-AFFINITY HETEROTRIMERIC IL-2 Receptor.

Therefore, the heterotrimeric receptor only present on activated T cells.

Question 26

Activated T cells express the high affinity IL-2 receptor, while also ________ IL-2.

The IL-2 binds to its receptor, promoting accelerated ____ ______.

IL-2 modulates T-cell _____ and enhances ________.

Thus activated T cells _______, ______, and _______ to IL-2.

Answer 26

secreting

cell cycling

differentiation; poliferation

express, secret; respond

Question 27

(T/F) Different helper T cells secrete specific cytokines to specific immune cells so that those cells change their behaviour based on the immune response needed.

Answer 27

True!

*CD8 T cells just directly kill virus-infected cells.