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HDM Final > T Cell Mediated Immunity > Flashcards

T Cell Mediated Immunity Flashcards

1
Q

Lymphocyte Activation

A

1st step- antigen presentation

Signal 1- antigen receptor and microbial

Signal 2- molecule induced by innate response (i.e. complement fragment)

Leads to lymphocyte proliferation and differentiation —> adaptive immune response

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2
Q

Outline: T cell activation

A

T cell activation stages:

(In lymphoid organs)
Antigen recognition (binding of Naive CD4 T cell) —> Activation (IL-2 binds to IL-2R on CD4+) —> clonal expansion —> differentiation —> moves to peripheral tissues —> effector functions such as effector CD4+ T cell (leading to activation of macrophages, B cells, and other cells), memory CD4+ T cell

Same is true for CD8+ T cells, except effector CD8+ cells —> kill infected target cells, macrophage activation and make memory cells

After T cells clear the infectious agent, the expanded population of lymphocytes apoptose

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3
Q

Mature Naive T cells

A

Resting mature naive T cells express

  • CD4 or CD8
  • CD28
  • HLA class 1
  • TCR complex inflicting CD3 molecules (signaling molecules)
  • LFA-1 and VLA-4 adhesion molecules
  • Chemokine R
  • CD25 —> during activation highly expressed
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4
Q

Naive T cell Responses are Initiated in Peripheral Lymphoid Organs

A

T cells circulate via HEV in lymph and are activated in the lymph nodes (circulate through LN to find Ag)

Innate immune responses aid in initiation of T cella activation through inflammation

DCs are the ONLY APC that activate mature naive T cells (B cells and macrophages activated memory T cells)

CD4+ T cells are responsible for activating B cells and macrophages

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5
Q

Naive T cells migration in the Peripheral Lymphoid Organs

A

Naive T cells enter the LN across the HEV in the cortex

T cells sample the Ag presented by APC

-T cells that do not encounter specific Af leave the node through the Lymphatics and travel down the chain to the next LN (surveillance) —> “death by neglect”

-T cells that encounter Ag proliferate and differentiate into effector cells
CD4+ cells increase by 100x to 100x (influence immune response, increase cytokines)
CD8+ cells increase by 100,000x

*excellent chart and table on slide 9

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6
Q

Accessory Molecules of T Lymphocytes

A

*R and signaling molecules of CD4 lymphocyte binding to ligands of class II MHC expressing APC

Signal Transduction- CD4, binds to class II MHC

Ag Recognition- TCR (a,B) binds with peptide and Class II MHC

Signal transduction- CD3, ITAM (“up”)(on CD3), zeta; CD28 (co-stimulator), and CTLA-4 which binds B7-1, B7-2 aka CD80 *(CTLA-4 is also INB)
PD-1 and ITIM (“down”)(on PD-1) binds to PD-L1/PD-L2 (INB signals)

Adhesion- LFA-1 binds to ICAM-1

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7
Q

Integrin Avidity increases upon Ag Recognition by T cells

A

TCR/HLA Ag recognition changes integrin conformation on T cells from low affinity to high affinity changing adhesion molecules and firm adhesion for immune synapse

1st signal—recognition of Ag
Integrin of T cells bind with low affinity to ligand on APC (no T cell response) —> chemokines from APC are released and bind to T cell, this signal delivered by chemokines and Ag recognition act on integrins —> integrins now have a high affinity and unregulated the receptors on T cell and ligand on APC, integrins cluster making a very tight bind

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8
Q

Role of Co-Stimulatory Molecules in T Cell activation

A

2 signals for complete activation

1st- binding of MHC/peptide complex to TCR (T cells recognize Ag with or without B7 costiumlators)

Expression of B7/CD80 unregulated on AC, CD28 is constitutively expressed on T cells

2nd signal-CD40L expressed unregulated on T cells, CD40 is constitutively expressed on APC (leads to DC activation) (complete stimulation)

DC expresses B7 and secretes cytokines, which enhance T cell activation—> enhances T cell proliferation and differentiation

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9
Q

T Cell Activation

A

Initiation of the IC signaling
1. Invitation of formation of the immunologic synapse
2. Activation of two tyrosine kinases
A. Activation of the tyrosine kinase Fyn leading to phosphorylation of the ITAMs of CD3y, d, e, and z chains
B. Like, the Sec family kinase associated with co-receptors CD4 and CD8 phosphorylation and activates the tyrosine kinase ZAP-70 that is associated with the z chain.

*good picture on slide 14
T cell receptor intracellularly —> phosphorylates ITAM —-> which phosphorylates ZAP-70 (specific zeta) —> phosphorylates PLCy1 which can start 3 reactions

PLCy1 activation —> increased cytosolic Ca2+ released from ER —> calcineurin —> NFAT (increases IL-2, nuclear factor of activated T cells)

PLCy1–> diacylglyercol (DAG) —> PKC
GTP/GDP exchange on Ras and Rac —> Ras-GTP, Rac-GTP —> ERK and JNK
Activation of P13-Kinase —> PIP3 —> Akt, mTOR —> increase protein synthesis (for interaction on APC)
All these 3 —> NFkB and AP-1 (activating protein 1

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10
Q

Activation of T Cells Triggers a Cascade of Protein Production

A

Membrane effector molecules
CD40 ligand- hours
Fas ligand- hours to express

IL-2- hours
IFNy- hours to days
IL-4- hours to days

Cytokine IL-2R/a-CD25—> hours

CD40L increases on T cells and interacts with CD40 on APCs to strengthen adhesions hence prolonging T cell APC contact

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11
Q

Induction of Anergy

A

T cells recognizing Ag without binding of co-stimulatory ligands or cytokine support will not become activated

They will become unresponsive—> anergic, tolerance (to self Ag, unless APC have been activated they should not express co-stimulators)

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12
Q

Cytokines produced by T cells

A

IL2- T cell proliferation regulatory T cell survival; activated T cells

IFNy- activation of macrophages; CD4 and CD8 T cells, NK cells

IL4- B cells switching to IgE; CD4 T cells, mast cells

IL5- activation of eosinophils; CD4 T cells, mast cells, innate lymphoid cells

IL17- stimulations of acute inflammation; CD4 T cells, other cells

IL22- maintenance of epithelial barrier function; CD4 T cells, NK cells, innate lymphoid cells

TGFB- INB of T cell activation, differentiation of regulatory T cells; CD4 T cells, many other cell types
*IL-10 and T refs, and Mo same as above for TGF-B

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13
Q

Promoting proliferation: self-stimulation by IL-2

A

IL-2 is an autocrat signa
IL-2 binds IL-2R
IL-2R is constitutively expressed as a low affinity receptor
Binding of IL-2 to high affinity IL-2R promotes T cell proliferation and differentiation
IL-2a chain= CD25

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14
Q

Cross presentation is often necessary for CD8 T cell Activation

A

CD8 T cells, and CD4 recognize Ag on APC that has ingested infected cell A. Infected cell —> (phagocytose by host APCs, with costimulation) —> DC and CD4 helper T cell- releases IL2 —> phagocytose cell

CD8 T cells recognize Ag on infected APC B. DC B7 binds to CD28 —> effector CTLs (clonal expansion and differentiation)

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15
Q

Trapping and Activation of Naive T cells

A

Within 2 days of an Ag appearing in a lymph node, it has been bound by its naive Ag specific T cell

Transient expression CD69- binds to S1PR and impairs migration “trapped”

Five days after the arrival of the Ag, activated effector cells emigrate from the LN into the periphery

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16
Q

Differentiation into Th, subsets dictated by the Cytokines Present

A

All T helper subsets are defined by CD4

IFNy and IL-12- Th1 (intracellular, Mo)
IL4, 5, and 13- Th2 (activate eosinophils, mast cells, and alternative macrophages)
TFGB, IL-6, and IL-23- Th17 (extracellular)
IL-21 (IFNy/IL4)- Tfh (help complete B cell activation)

17
Q

T Helper 1

A

IL-12 and IFN-y —> TBET —> Th1 —-> IL-2, IFN-y, also TNF-a

18
Q

Th1 cels are characterized by INF-y secretion

A

IFN-y

  • activated macrophages against IC microbes (classical activation)
  • Activates B cells to stimulate complement binding and class switching
  • Stimulates class II HLA and B7 (CD80) expression (IFN-y stimulates class II HLA)
  • TNF-a is also produced by Th1 cells
19
Q

T Helper 2

A

-Proliferates in response to IL-4
-Occurs in response to allergens and helminths
-Novel transcription factor GATA-3
Secrete IL-4, IL-5, IL-13
(Autocrine amplification)

Allergens and Helminths —> IL-4 —> GATA-3 —> Th2 —> IL-4 (change to IgE), IL-5 (leads to development of eosinophils), IL-13

20
Q

Th2 cells Mediate Phagocyte-Independent Immunity

A
  • Stimulate IgE, mast cell, and eosinophils reactions that eradicate helminths
  • Isotype switching —> IgE
  • Support alternative macrophage development
  • Secrete IL-4, IL-13, and IL-5
21
Q

T Helper 17

A
  • Proliferate in response to IL-1 and IL-6
  • Response to bacteria and fungus (EC)
  • Induction of inflammation and leukocyte recruitment
  • Novel transcription factor RORyt
  • Secrete IL-17 and IL-22

Bacteria and fungus —> IL-1 and IL-6 —> RORyT — IL-17 (super inflammatory) and IL-22 (help maintain barriers)

22
Q

Th17 Cells are characterized by IL-17 production

A

First described in animal models of disease i.e. multiple sclerosis, IBS, and RA

Destruction of EX bacteria and fungi by inducing neutrophilic inflammation

Important in barrier function and neutrophil activation

23
Q

Migration of activated Th Cells

A
  • After activation by APCs in the medullary area, CD4+ Th cells change their chemokine receptor expression and migrate to the edge of the follicular zone
  • Activated Th cells secrete low levels of cytokines and increase expression of co-stimulators molecules
  • Activated T cells start expressing CTLA-4

Ag presentation, T cell activation —> decrease in CCR7 (used to come into cell) and increase of CXCR5 (B migration R) and migration of activated T cells to edge of follicle—> B cells present Ag to activated helper T cells —> Ag uptake and processing, B cell activation, CCR7 increase (for B cells to move towards T cells), and migration of activated B cells to edge of follicle

CCR7 is downregulated for T cells because it needs to find B cells and present, easier if the two cells aren’t both moving so much

24
Q

Cytokine Influence on class switching

A

Recognize that class switching can happen

Naive B cell+LPS—> no isotype switching
Naive B cell+LPS+IL-4 —> IgE?
Naive B cells+LPS+TGFb—>IgA?

25
Q

Cytokine influence of Th development

A

Each subset produces cytokines that support its own development and suppress others

Differentiation of each subset is induced by the types of microbes it is best able to combat

26
Q

T Regulatory Cells

A

CD4+ T cells

Constitutively express CTLA-4, CD25

Novel transcription factor FOXp3 (think military regulates)

CTLA-4 binds B7 and shuts down IL-2 production

Binds more avidly than CD28

Secrete IL-10 and TGF-b

IL-2 and TGFB—> FOXp3 —> TReg—> IL-10 and TGF-B

27
Q

Gamma Delta T Cells (increase in mucosa- whatever is in contact with outside world)

A

Less than 5% of Ts

Found in higher numbers at epithelial boundaries

Ag restricted

  • Limited diversity of peptides recognized
  • can recognize non-protein Ag (DAMPs)
28
Q

CD4+ T help for CTL development

A

Cytokine support for activation and proliferation of CTLs

Induction of cytotoxic protein synthesis

Activated CD8+ effector T cells not sequestered (perform their function- go out and kill)

CD4+ helper T cells produce molecules that stimulate CTL differentiation, secrete IFNy and IL2

29
Q

Th1/Th2 cytokine influence on disease

A
  • Th1 effector T cells are necessary to combat IC microbes
  • A predominant Th2 response to an IC microbe can lead to poor disease outcomes (like Terculoid leprosy and lepromatous leprosy)
30
Q

Clinical Blue Box- CIS case of Ursula Iguaran

How do you change someone who is predominantly Th2

A

Normal numeral response, biopsy reveals high amount of neutrophils and Mo and few lymphocytes

Why is Ursula prone to Asthma?
It is an allergy, Th2 —> IL-5, IL-4 —> IGE

Treat with IFNy —> increase macrophages (type 1)
This allows the own body’s macrophages to activate and kill bacteria to have a better controlled response

Th1 cytokines —> high levels of IL-2, IFNy, and TNF-b—> turberucloid form

Th2 —> high levels of IL-4 IL-5 and IL-10 —> lepromatous form (more severe)

31
Q

Leprosy

A
  1. Cutaneous lesions
  2. Neuropathic changes
  3. Deformities

M. Leprae colonizers Mo and other host cells and multiples within them

Can only be eliminated by IC killing by activated Mo (similar to TB)

Grows best at 86 degrees, hence predominant growth of lesions on extremities

Clinical symptoms vary depending on the type if mine response

HDM Final (4 decks)

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