Effector Mechanisms of T Cell Immunity

Question 1

CD8 Cytotoxic T Lymphocytes (CTL)

Answer 1

• CD8 Cytotoxic T Lymphocytes (CTL) can recognize peptide antigen (e.g. viral peptide) on any cell that expresses MHC class I (which is ALL nucleated cells).
• Each differentiated CTL will then kill the recognized cell displaying the target peptide-MHC complex. This prevents replication and spread of the virus, which uses the infected cell as a virus factory.

Question 2

CD4 T helper Lymphocytes (TH)

Answer 2

• CD4 T helper Lymphocytes (TH) are functionally divided into several subsets of T cells: TH1, TH2, TH17, TREG and more. These cells originate from the uncommitted and “plastic” naïve TH0 cell.
• Each CD4 subset has its’ own master transcriptional regulator, which, once induced in the TH0 cell during activation, controls the differentiation program that restricts which kinds of cytokines will be produced by the cell.

Question 3

TH1 cells secrete [].

Answer 3

TH1 cells secrete IL-2, IFN-g and TNF-a.

• TH1 cells secrete IL-2, IFN-g and TNF-a to help a cellular response against intracellular pathogens. IFN-g activates CTL, macrophages and natural killer cells, and can also have direct antimicrobial activity.
• Like CD8+ cytotoxic cells, they express the master transcription factor T-bet.

Question 4

• TH2 cells secrete [].

Answer 4

• TH2 cells secrete IL-4, IL-5, IL-10 and IL-13.

•TH2 cells secrete IL-4, IL-5, IL-10 and IL-13 to help an antibody-mediated response to clear extracellular parasites, including helminths. Express master transcription factor GATA-3.

Question 5

TH17 cells secrete [].

Answer 5

TH17 cells secrete.

•TH17 cells secrete IL-17 and IL-22 that play a role in mucosal and skin immunity to extracellular pathogens (bacteria, fungi). They are now believed to be key players in autoimmunity (arthritis, IBD, etc.). Express master transcription factor RORgt.

Question 6

TREG cells express [].

Answer 6

TREG cells express CTLA-4 and/or IL-10.

•TREG cells express CTLA-4 and/or IL-10, which down-regulate or modulate the activation of other T-cells. This population expresses CD25 on the cell surface and FoxP3, the master TREG transcription factor.

Question 7

Naïve T cells express the adhesion molecule [], and the chemokine receptor [].

Answer 7

Naïve T cells express the adhesion molecule L-selectin (CD62L), and the chemokine receptor CCR7.

• . These molecules mediate their selective migration into lymph nodes through high endothelial venules (HEVs).
• HEVs express carbohydrate ligands for CD62L, which allow the naïve T cells to slowly roll along the vessel wall.

Question 8

HEVs express [] ligands for CD62L, which allow the naïve T cells to slowly roll along the vessel wall.

Answer 8

HEVs express carbohydrate ligands for CD62L, which allow the naïve T cells to slowly roll along the vessel wall.

Question 9

HEVs also display the chemokines [] and [], which bind to [] on naïve T cells. Then what happens?

Answer 9

HEVs also display the chemokines CCL19 and CCL21, which bind to CCR7 on naïve T cells.

• CCR7 ligation leads to upregulation of the integrin LFA-1 on the naïve T cell, which can then tightly bind ICAM-1 on the HEV, leading to arrest of the naïve T cell within the vessel.
• The naïve T cell can then exit the vessel through the endothelial junctions to enter the T cell zones of the lymph node.

Question 10

Following activation, effector T cells lose expression of CD62L and CCR7, allowing their [].

Answer 10

Following activation, effector T cells lose expression of CD62L and CCR7, allowing their .

Question 11

Activated T cells gain expression of [] and [] that interact with molecules expressed by vascular endothelial cells at sites of inflammation. What are these molecules?

Answer 11

activated T cells gain expression of adhesion molecules and chemokine receptors that interact with molecules expressed by vascular endothelial cells at sites of inflammation.

•These molecules (E- and P-selectins, LFA1, VLA-4) are the same as what other leukocytes use to migrate into tissues in response to inflammation at early time points after infection

Question 12

Is the homing of effector T cells to sites of infection antigen specific or non specific?

Answer 12

The homing of effector T cells to sites of infection is NOT antigen-specific, but simply driven by the same recruitment strategy of other leukocytes in response to inflammatory signals. Only pathogen-specific T cells will be retained at those sites upon antigen recognition.

Question 13

What is a major role for Th1 cells?

Answer 13

A major role for TH1 cells is the activation of macrophages for effective killing of phagocytosed/intracellular microbes.

Question 14

Macrophages are activated by [], and become further sensitive to[], after ligation of [] on the macrophage – both of these signals can be provided by TH1 cells.

Answer 14

Macrophages are activated by IFNg, and become further sensitive to IFNg, after ligation of CD40 on the macrophage – both of these signals can be provided by TH1 cells.

Question 15

Upon full activation, macrophages gain several properties to enhance the clearance of pathogens:

Answer 15

• Production of reactive oxygen species, nitric oxide, and increased production of lysosomal enzymes to enhance killing of pathogens within phagolysosomes.
• Secretion of cytokines to promote inflammation and leukocyte recruitment (TNFa, IL1), as well as maintain TH1 polarization/differentiation (IL-12).
• Upregulated expression of MHC and costimulatory molecules to become more efficient at antigen presentation to T cells.

*As activated TH1 cells are the main source of IFNg for macrophage activation, and these macrophages provide IL-12, MHC, and costimulatory expression back to CD4 T cells, there is an amplification/ cross-talk loop that occurs between these populations during an active infection

Question 16

What is a major role for Th2 cells?

Answer 16

• TH2 cells are abundant producers of IL-4, which is critical for the production of the IgE class of antibodies.
• IgE is bound to tissue mast cells and eosinophils.
• In their key role in production of IgE, TH2 cells aid defense against large extracellular helminthic parasites (which are too large to be phagocytosed by macrophages). Upon encountering antigen, crosslinking of IgE molecules (on mast cells or eosinophils) leads to degranulation of the mast cell/eosinophil, releasing large amounts of toxic granules onto the parasite. In the gut, mast cell activation leads to peristalsis and mucus secretion to aid in expulsion of the parasite.
• TH2 cells can also produce IL-5 to directly activate eosinophils.
• Finally, TH2 cytokines promote alternative macrophage activation (M2), which promotes wound repair.

Question 17

Th2 produces [] which stimulates production of IgE and [] which stimulates eosinophils.

Answer 17

Th2 produces IL 4 which stimulates production of IgE and IL 5 which stimulates eosinophils.

Question 18

What is a major role for Th17 cells?

Answer 18

•TH17 cells are important producers of cytokines that aid neutrophil recruitment into sites of infection.

Question 19

Th17 cells are highly enriched in the gut mucosa and seem to play a critical role in immune defense against extracellular bacteria (via []) in this tissue, as well as throughout the organism

Answer 19

Th17 cells are highly enriched in the gut mucosa and seem to play a critical role in immune defense against extracellular bacteria (via IL-17) in this tissue, as well as throughout the organism

Question 20

[] produced by TH17 cells are key in maintaining the functional integrity of the epithelia, helping to preserve barrier function in the gut.

Answer 20

IL 22 produced by TH17 cells are key in maintaining the functional integrity of the epithelia, helping to preserve barrier function in the gut

Question 21

What is a major role for Threg cells?

Answer 21

TREG cells are a heterogeneous population that suppresses the activity of the other effector T cell populations, helping to control immune responses, and prevent the development of autoimmunity.

Question 22

What are the two classes of Treg cells?

Answer 22

• Natural Treg cells
• Induced Treg cells

Question 23

Natural TREG: develop in the thymus from self-reactive T cells that express conventional ab TCR that respond with high affinity to self-peptide: MHC complexes. They suppress the proliferation of other T cells by both contact-dependent means ([]), and through the secretion of [] and [].

Answer 23

Natural TREG: develop in the thymus from self-reactive T cells that express conventional ab TCR that respond with high affinity to self-peptide: MHC complexes. They suppress the proliferation of other T cells by both contact-dependent means (CTLA-4), and through the secretion of IL-10 and TGFb.

Question 24

Induced TREG: are more heterogeneous with several different subtypes characterized, including [] and [], as well as a [] population. These cells develop in the periphery by several distinct (but poorly understood) mechanisms. They may or may not express the FoxP3 transcription factor.

Answer 24

Induced TREG: are more heterogeneous with several different subtypes characterized, including TH3 and TR1, as well as a CD8 TREG population. These cells develop in the periphery by several distinct (but poorly understood) mechanisms. They may or may not express the FoxP3 transcription factor.

Question 25

CD8 Cytotoxic T Lymphocytes (CTL) can recognize peptide antigen on any cell that expresses MHC class I. The CTL enter the site of inflammation via integrin such as [] and adhesion molecule, [] interaction.

Answer 25

CD8 Cytotoxic T Lymphocytes (CTL) can recognize peptide antigen on any cell that expresses MHC class I. The CTL enter the site of inflammation via integrin such as LFA1 and adhesion molecule, ICAM-1 interaction.

Question 26

Two Ways the CD8 cell kills:

Answer 26

1. Pore formation: Perforin (stored in granules) forms pores in the target cell membrane. This can lead to leakage of the intracellular content. In addition, such pores are used by CTL to inject Granzymes (serine proteases) that enter the cell and induce apoptosis.
2. Apoptosis by Granzymes or by Death receptor signaling: As mentioned above, pores can be used to inject Granzymes, which induce apoptosis of target cells. Apoptosis can be also induced without pore formation, when the Fas ligand on CTL binds the Fas receptor (CD95) on target cells and induces DNA fragmentation.