(L24) T Cell Mediated Immunity

Question 1

What surface molecules do resting, naive T cells have? L24 S9

Answer 1

-CD4+ or CD8+ -CD3+ and ζ dimer -CD28+ -MHC class I -LFA-1 and VLA-4 (adhesion) -CCR7 (chemokine receptor)

Question 2

Where are resting, naïve T cells activated? What 3 steps are involved in their activation? L24 S10-11

Answer 2

Activated in lymph nodes primarily by DCs First signal generated by binding of TCR complex to peptide-MHC complex of APC. This stimulates expression of CD40L. CD40L activates APC causing it to express CD80 (B7) and produce cytokines. Second signal generated by binding of APC CD80 to T cell CD28. Third signal is APC cytokines binding T cell cytokine receptor

Question 3

What is the intracellular method of signaling during T cell activation? L24 S17

Answer 3

CD4/8 associated Lck phosphorylates ζ chain attracting ZAP-70 which is then also phosphorylated and activated. ZAP-70 phosphorylates LAT which attracts other molecules: -PLCγ1 -GRB2 -PI3-kinase Transcription factors produced are: -NFAT -NF-κB -AP-1

Question 4

What happens to a T cell that has bound presented Ag but is not costimulated? L24 S19

Answer 4

T cell is not activated and becomes anergic

Question 5

What cytokines are made by T cells? (7) L24 S20

Answer 5

IL-2 IFN-γ IL-4 IL-5 IL-17 IL-22 TGF-β

Question 6

How does T cell production of IL-2 affect T cells and how is this regulated by the IL-2R? L24 S21

Answer 6

One of the functions of IL-2 is to stimulate T cell proliferation. T cells constitutively express a low affinity version of the IL-2R consisting only of the β and γ subunits When T cells are activated by costimulation with CD80 (B7), they express the α chain (CD25) of the IL-2R forming a high affinity IL-2R(αβγ).

Question 7

How are T cell retained in the lymph nodes while being activated? L24 S22

Answer 7

CD69 is expressed by T cells in the lymph node while they are being activated. CD69 binds S1PR (sphingosine 1-phosphate receptor) which is responsible for egress of T cells from the lymph nodes. Because S1PR cannot bind S1P, which is found in the blood outside the lymph node, it cannot leave until CD69 is removed at the end of activation.

Question 8

What are the main types of helper T cells and what cytokines stimulate their differentiation? What is the main function of and effected cell of these types? L24 S25; 30

Answer 8

Th1 (regulates macrophages, intracellular pathogen defense): -IFN-γ -IL-12 Th2 (regulates eosinophil response, helminth defense): -IL-4 -IL-5 -IL-13 Th17 (regulates neutrophils, extracellular defense): -TGF-β -IL-17 -IL-22 Tfh (regulates B cells, antibody production and isotype switching): -IL-21 -IFN-γ (IgG) or IL-4 (IgE)

Question 9

How are T helper cells involved in activation of CTLs? L24 S26

Answer 9

Helper T cells (Th1), when presented Ag by APCs, “license” the APC to activate CTLs by producing IFN-γ which causes production of costimulation CD80 (B7) on the APC which is required for CTL activation. Helper T cells also produce IL-2 which stimulates CTL proliferation

Question 10

What are the characteristics of T reg cells and what are its mechanism of action? What transcription factor is novel to T reg cells? L24 S30

Answer 10

Subtype of T helper cells that express the transcription factor FOXp3. They constitutively express CTLA-4 and CD25 (IL-2Rα) They secrete IL-10 (anti-inflammatory) and TGF-β (inihibts T cells activation; stimulates T reg cells) CTLA-4 binds CD80, preventing it from activating other T cells IL-2Rα associates with IL-2Rβγ forming high affinity IL-2R receptor which binds IL-2 preventing it form activating other T cells

Question 11

What is the major difference between naïve T cells and effector T cell? L24 S34

Answer 11

Naïve T cells require costimulation with CD80 (B7) to be activated. Effector T cells do not require costimulation to activate effector functions.

Question 12

What cytokines stimulate Th1 development and what is the transcription factor? What cytokines are produced by Th1 cells and what are the effects? L24 S35-36

Answer 12

Stimulated by: -IL-12 -IFN-γ Transcription factor: T-bet Cytokines produced: -IL-2 (T cell stimulation, Treg survival) -IFN-γ (classical Mφ activation, B cell IgG class switching, expression of CD80 on APCs)

Question 13

What cytokines stimulate Th2 development and what is the transcription factor? What cytokines are produced by Th2 cells and what are the effects? L24 S38-40

Answer 13

Stimulated by: -IL-4 Transcription factor: GATA-3 Cytokines produced: -IL-4 (B cell IgE class switching, alternative Mφ activation w/ IL-13, increased mucous secretion and peristalsis) -IL-5 (eosinophil activation) -IL-13 (alternative Mφ activation w/ IL-4, increased mucous secretions and peristalsis)

Question 14

Which T helper cell response is preferred in combating an infection and why? L24 S42

Answer 14

Th1 response is preferred as it stimulates microbicidal activity of Mφ. Th2 response inhibits this function and often lead to poor disease outcome.

Question 15

What cytokines stimulate Th17 development and what is the transcription factor? What cytokines are produced by Th17 cells and what are the effects? L24 S43-44

Answer 15

Stimulated by: -IL-1 -IL-6 Transcription factor: RORγt Cytokines produced: -IL-17 (proinflamatory response, neutrophil attraction, antimicrobial peptide production) -IL-22 (increase barrier function, antimicrobial peptide production)

Question 16

How are Ag specific T cells retained in peripheral tissue? L24 S48

Answer 16

Expression of selectins and integrins: -VLA-4 which binds VCAM-1 -P and E selectin ligands which bind tissue P and E selectin -CD44 which binds hyaluronic acid

Question 17

What are the effector mechanism of CD8+ T cells (CTLs)? L24 S51-53

Answer 17

Grangzyme/perforins: -release of stored granzymes and perforins form CTL -perforins forms pore in target cell membrane -granzyme enters through pore and acts as pro-apoptotic factor Fas/FasL: -CTL expresses Fas -certain cell types express FasL which when bound to Fas stimulates apoptosis

Question 18

What are the surface markers of NK cells? What is their effector mechanisms? What regulates their function? L24 S56

Answer 18

Markers: -CD16+ CD56+ Antibody-dependent cell-mediated cytotoxicity (ADCC): -release of stored granzymes and perforins form NK stimulates by binding of IgG to FcγRIIIB (CD16) -perforins forms pore in target cell membrane -granzyme enters through pore and acts as pro-apoptotic factor Function is inhibited by the presence of MHC class I Function enhanced by class I interferons (α and β) and IL-12

Question 19

How does CTLA-4 regulate T cell activation? L24 S61

Answer 19

CTLA-4 is constitutively expressed following binding of TCR to Ag. CTLA-4 binds to CD80, which is also the ligand for CD28 (costimulatory receptor). It generates an inhibitory signal. Because CTLA-4 is inhibitory and expressed proportionally to TCR stimulation, it acts to dampen the T cell activation so it is not over stimulated. I does this through it inhibitory signaling as well as competitively binding CD80 preventing it from bind CD28 and generating a stimulatory signal.

Question 20

What are memory T cells and how do the differ from naive T cells? What cytokines are required for memory T cell survival? L24 S59;62

Answer 20

Memory T cells are cells that have been activated in an immune response and then survived contraction of T cell population following the resolution of the infection. They are dormant and long lived but will reactive when exposed to Ag. Memory T cells react more rapidly upon rexposure to Ag than naïve cells do. Require IL-7 and IL-15 for survival

Question 21

What is T cell exhaustion? When and how does it happen? L24 S63-64

Answer 21

When T cells remain active for extended periods of time, as in chronic infections, they accumulate CLTA-4 and PD-1 on their membranes. If enough CTLA-4 and PD-1 accumulator, the inhibitory signals strengthen and weaken or eliminate the response of the cell.