12. Effector Lymphocytes

Question 1

Primary activation of naive T cells requires Ag:MHC (signal 1) and costimulatory molecules (signal 2). what does hte effector function require?

Answer 1

Ag:MHC (signal) 1 only!

Question 2

stimulation of cells within the node increases the expression of certain cell surface molecules on the blood vessels associated with the lymph nodes. These vessels are called what?

Answer 2

high endothelial venules (HEV)

Question 3

lymphocytes circulating the in blood bind to the HEV surface primarily through what?

Answer 3

selectins and integrins on cell surface (and the migration of lymphocytes REGARDLESS OF ANTIGEN SPECIFICITY) into the node is greatly enhanced - this is why draining lymph nodes get large with infection

Question 4

what type of cells are in the lymph node follicles?

Answer 4

B cells and FDC (follicular dendritic cells)

Question 5

In T cell zones, what cells are present?

Answer 5

T cells and class II-expressing DCs (the professional APCs)

Question 6

CD4 can be further divided into T helper subsets (Th1, Th2, Th17, etc) which are discriminated primarily by what?

Answer 6

cytokines they secrete after activation and during effector function

Question 7

where does the effector function of T cells occur? (CD4 and CD8)

Answer 7

site of infection (requires only Signal 1!)

Question 8

when are antigen-specific lymphocytes released from the lymph node?

Answer 8

after activation (3-5 days after antigen exposure)

Question 9

what are the important T cell Lymph node homing receptors?

Answer 9

LFA-1 (binds to ICAM) or VLFA-4, CD62L (L-selectin), and CCR7 (binds to CCL19/CCl21)

Question 10

activated T cell shave _____ which is capable of binding to CXCL10 that allow T cells to leave the blood stream and to go out into tissue to exert the immune response.

Answer 10

CXCR3

Question 11

____ allows for rolling/tethering.

Answer 11

selectin

Question 12

_____ allows for simulation/signaling.

Answer 12

chemokines

Question 13

_____ allows for firm adhesion.

Answer 13

integrin

Question 14

4 steps of leukocyte trafficking

Answer 14

1. tethering (selectins)
2. activation (chemokines)
3. adhesion/arrest (integrin/CAM)
4. transendothelial migration (diapedesis)

Question 15

how do chemokines affect adhesion?

Answer 15

inside-out signaling

chemokines signal from the inside to change the conformation of integrins (make them high affinity) on the outside of lymphocytes

Question 16

migration of lymphocytes is dictated by their combination of what?

Answer 16

selectin, chemokine receptor, and integrin

Question 17

lymph node-homing cells (naive and central memory cells) can be identified by their expression of what?

Answer 17

CD62L (L-selectin) and CCR7

Question 18

CD8 cells require activation from D cells and help from CD4 cells - what are the two models for this requirement?

Answer 18

1. CD4 cells and CD8 cells recognize antigen on the same DC
2. armed CD4 cells (ie CD40L-expressing CD4 cells) activate quiescent DC to upregulate costimulatory molecules, a phenomenon known as DC licensing

Question 19

For effector cell function, no 2nd signal is required just the recognition of the antigen/MHC class I complex by the killer T cell. Therefore, only naive T cells that have recognized antigen in the presence of a 2nd signal gain effector function - why go through all of this trouble to activate cells?

Answer 19

to preserve self tolerance

(Recall that class I molecules are expressed by almost all cells of the body and thus can display peptides—mainly derived from viruses or other cytosolic pathogens (or any self protein !) - for recognition by activated CD8 cells, especially at epithelial surfaces.  Any self antigen that can be presented by self MHC is a potential target and not all self antigens are expressed by the thymus for selection.  By requiring Signal 2 for proper activation, one can avoid responses by self-reactive mature T cells in the periphery since recognition of Signal 1 in the absence of Signal 2 induces anergy (inactivation) of naïve T cells.
)

Question 20

when CTLs bind their targets, they lyse them by one of what pathways?

Answer 20

1. a molecule found in granules called perforin (which is homologous to complement C9) polymerizes upon release from CTL onto an infected cell and effects osmotic lysis of the infected cell, but this is a minor pathway
2. a molecule found in granules, granzyme B, can enter the infected cell (through perforin pores) and induce programmed cell death cascades in those cells, which is considred the major pathway
3. CTL expressing a molecule called FAS-Ligand can bind to FAS on other cells and induce programmed cell death
4. cytotoxic cytokines such as TNF and lymphotoxin (LT) secreted by CTL in close proximity to infected cells can induce lysis

Question 21

CD8 cells also mediate immune response to what type of pathogens and give examples?

Answer 21

intracellular pathogens: mycobacteria, listeria, cryptococcus, rickettsia by producing some inflammatory cytokine alpha (IFN-gamma)

Question 22

perforin deficiency causes what?

Answer 22

Hematophagocytic lymphohistiocytosis (HLH)

• genetic or acquired (infection)
• fever, splenomegaly, haemophagocytosis, hypertriglyceridaemia, and hypofribrinogenaemia
• high serum levels of IFN-gamma, TNF-alpha, IL-6, IL-10, and M-CSF

Question 23

anti-IFNgamma is a a proposed treatment for what?

Answer 23

HLH (reverses the toxicity associated with the loss of perforin)

Question 24

how specific is CTL killing of targets?

Answer 24

one CTL can kill multiple targets

Question 25

activation and differentiation of naive CD4 cells to effector T helper cells (Th1, Th2, Th17, iTreg) occurs where?

Answer 25

secondary lymphoid tissues

Question 26

exposure of IL-12 (or IFN-gamma) drives which T helper?

Answer 26

Th1

Question 27

exposure to IL-4 drives which T helper?

Answer 27

Th2

Question 28

exposure to IL-6 and TGFbeta and IL-23 drives which T helper?

Answer 28

Th17

Question 29

What do Th1 cells do?

Answer 29

produce IFNgamma and TNFalpha to stimulate phagocyte-mediated defense against intracellular pathogens (classically called delayed type hypersensitivity, DTH)

Question 30

what do Th2 cells do?

Answer 30

Th2 cells produce IL-4, IL-5, and IL-13 which are involved in the activation, proliferation and differentiation of B cells and growth of eosinophils and basophils. Thus the Th2 cells are most important for defense against extracellular pathogens (predominantly parasites) that can be attacked by specific antibodies or destroyed by activation of mast cells and eosinophils. Furthermore, the cytokines produced by either Th1 or Th2 cells suppress the formation of the other type during an immune response.

vs. helminths, staphylococcus, and clostridium (extracellular pathogens) & allergy

Question 31

what do Th17 cells do?

Answer 31

Th17 cells secrete IL-17 (thus the name) and IL-22. Th17 cells seem to stimulate neutrophils to migrate to sites of infection in a typical inflammatory response; this stimulation is indirect, working through intermediary cells like endothelial cells and fibroblasts. Thus, unlike the direct stimulation of hematopoietic cells by Th1 and Th2 cells, Th17 does not stimulate its final cellular target in a cognate fashion.

kill extracellular bacteria like klebisella, S. aureus, fungi, and aspergillus….only acts indirectly to enhance phagocytosis and not on the neutrophil itself

Question 32

what do Treg cells do?

Answer 32

induced by TGF-beta and IL-10 and secrete TGFB and IL-10….uses FoxP3

“induced or adaptive Treg, (iTreg)” also can be stimulated under the right conditions from a naïve CD4 cell. Such cells produce TGFbeta and IL-10 and are believed to be important in dampening responses to foreign antigens.

Question 33

what do nTreg cells do?

Answer 33

“natural Treg (nTreg)” that, unlike Th1, Th2, Th17, and iTreg, differentiates in the thymus. Natural Treg seem to be selected on self antigens in the thymus, and are believed to “stand watch” over autoaggressive lymphocytes in peripheral tissues.

Question 34

dominant leukocyte recruited by Th1, Th2, and Th17?

Answer 34

Th1 - monocytes
Th2- eosinophils
Th17 - neutrophils, monocytes

Question 35

Job’s syndrome

Answer 35

Hyper IgE syndrome (HIES) - Job’s is a defect in STAT3 and Th17 (and others)

Mutations in STAT3 can lead to a disease in which there are high levels of IgE in the serum (usually there is essentially no IgE), and a defect in the elimination of extracelluar bacteria leading to S. aureus skin abcesses (leading to boils, like Job’s) and bacterial pneumonia. Defect in STAT3 signaling through the IL-6 and IL-23 receptor can help to explain the lack of IL-17 cells, since IL-6 and IL-23 are inductive factors for TH-17 cells. The defect in IgE synthesis is not understood, but since STAT3 is associated with other signaling receptors, like IL-21 which is important in B cell stimulation by Tfh cells, there may be a problem with regulation of the Ig class switch (see next lecture).

Question 36

mutations in ____ lead to defects in IL-6 and the Th17 lineage in Job’s syndrome.

Answer 36

STAT3 (loss of STAT3 funciton which is autosomeal dominant inhibits Th17 development)

Question 37

what are the hallmarks of memory cells?

Answer 37

they are long-lived, antigen specific cells that respond more rapidly and more vigorously than naive lymphocytes (responses of antibody production, cytokine secretion and even proliferation that occure more rapidly than primary response by naive cells)

Question 38

what happens with chicken pox and shingles?

Answer 38

get antibodies and T cell response isnt enough to keep intracellular pathogens in check