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HDM Final > Effector Mechanisms Of T Cell Immunity > Flashcards

Effector Mechanisms Of T Cell Immunity Flashcards

1
Q

Overview of T Lymphocyte Activation

A

Lymph Nodes

  • Ag recognition
  • Proliferation and differentiation

Blood
- effector cells travel via circulatory system

Site of Infection

  • Ag recognition
  • Effector functions
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2
Q

Cell Mediated Immunity

A

Can transfer immunity to IC microbes to non-immune individuals by transferring “immune” T cells

IC microbes are killed by either CD8+ CTL or activated macrophages or “cells”

Immune serum does not protect against IC microbes

  • graph on T lymphocytes adoptively transfer specific immunity
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3
Q

The Major difference between effector T cells and Resting Naive T cells is…

A

An effector T cell is able to respond to specific Ag WITHOUT need for co-stimulation via B7-CD28 interaction

**think this is a high yield concept

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4
Q

Migration of CD4 T helper cells

A

Leave LN to perform effector function

  • Effector Th cells leave the Lymphatics and re-enter circulation
  • They circulate until they are exposed to inflammatory molecules that allow them to migrate into the peripheral tissues at the sight of infection

Ag recognition and induction of response in lymphoid organs —> T cell proliferation and differentiation —> differentiated CD4 Th cells enter circulation —> Migration of effector T cells and other leukocytes to site of Ag —> effector functions of T cells

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5
Q

Migration of CD8+ effector cells

A

Ag recognition in lymphoid organs —> induction of response —> T cell expansion and differentiation —> (leave via efferent) —> differentiated CD8+ CTLs cells enter circulation —> effector CD8+ CTLs activated by Ag in peripheral tissues —> CTL killing of target cell

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6
Q

Effector T cell Migration site of Infection

A

Effector TSS enter the peripheral tissues by interacting with cytokines (follow SP1 into blood), chemokines, and adhesion molecules on the endothelium at the site of infection

The adhesion molecules and chemokines for effector Ts are different than the molecules on the HEV naive T cells interact with (want it to stay in the blood)

Not every effector T cells that enters the area will be specific for that Ag- selections and integrins are non-Ag specific

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7
Q

Ag specific T cells are retained in peripheral tissue with infection

A

New selectins and integrins are expressed upon activation

VLA- binds to ICAM and fibronectin
P&E selectin ligands
CD44- binds to hyaluronan

Retention of effector lymphocytes

Actions are less dependent on co-stimulation

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8
Q

Th1 cells are characterized by INF-y secretion

A

IFN-y

  • Activates macrophages against IC microbes —> classical activation
  • Activates B cells to stimulate complement binding and class switching (of Ab —> opsonization and phagocytosis)
    • Stimulates class II HLA and B7 expression
  • TNF-a is also produces by Th1 cells
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9
Q

Th1 phagocyte activation

A
  • Effector T helpers migrate to the area of infection
  • They “sample” Ag presented to them by macrophages
  • Immune synapse between T helper cells the macrophage fully activates the macrophage to become a better killer
  1. Activation of effector cell (macrophage with ingested bacteria, expresses CD40 and has IFNy receptor), binds with CD4+ effector T cell
  2. Activation of Macrophage (CD40L of T cells binds to CD40 of macrophage, T cell releases IFN-y, binds to macrophage)
  3. Responses of activated Mo (killing of phagocytose bacteria through ROS, NO, releasing of TNFa, IL-1, IL-2, chemokines, increases expression of MHC and costimulators aka B7 molecules)
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10
Q

Th2 Cells Mediate Phagocyte-Independent Immunity

A 
- Stimulate IgE, mast cell, eosinophils reactions that eradicate helminths
IL-4 —> isotype class switching —> IgE
IL-4 and IL-13 —> activates alternative macrophages and intestinal mucus secretion and peristalsis
IL-5 —> eosinophil activation
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11
Q

Th2 Immunity

A

Functions as protection against helminths

  • Mast cell activation
  • Mucus production
  • Peristalsis
  • IgA production??
  • Eosinophil activation

Real life application —> allergies (atopic D)

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12
Q

Th1 vs Th2 activation of Macrophages

A

Competitive INB on one another

Classically activates macrophage (M1) are activated by microbial TLR ligands and IFN-y—> ROS, No, lysosomal enzymes —> microbicidal actions, phagocytosis and killing of many bacteria and fungi
—> IL-1, IL-12, IL-23, chemokines —> inflammation

Alternatively activates macrophage (M2) —> IL-13, IL-4 —> M2 —> IL-10 TGF-B —> anti inflammatory effects, wound repair, fibrosis

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13
Q

Th17 Cells are characterized by IL-17 production

A
  • First described in animal models of diseases including multiple sclerosis, IBS, and RA
  • Destruction of EC bacteria and fungo by inducing neutrophilic inflammation
  • Important in barrier function and neutrophil activation

Naive CD4+ T cell —> (proliferation and differentiation) —> Th17 —> IL-17 and IL-22
IL-17 —> pro inflammatory
IL-22- maintains barrier function

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14
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 —> T cell decreases CCR7 (stop moving so much) and increases CXCR5 (B migration) 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, increase of CCR7 by B cells and migration of activated B cells to edge of follicle

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15
Q

Cytokine Influence on Class Switching

A

IL-4 —> IgB

TGF-B —> IgA

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16
Q

Cytotoxic T-Lymphocyte (CTL) Killing

A

-Cytotoxic CD8+ cells = CTL cells
-TCR recognizes MHC class I plus altered-self Ag (cells that have been transformed)
-Kill cells infected with IC pathogens or tumor-transformed cells
-Th1 effector cells enhance proliferation, differentiation, and cloning of activated CD8+ T cells by providing IL-2 — IFNy increase HLAMHC expression on CD8+
(IL-2 is growth factor for T cells)

17
Q

Overview of CTL function

A
  1. Ag recognition and conjugate formation
  2. CTL activation
  3. CTL granule exocytosis
    4 Apoptosis of target cell (controlled death— no PAMPs released)
  • Ag specific, MHC I restricted cytotoxicity
  • Involved in the killing of IC pathogens
  • Host cell must be killed to eliminate the pathogen
  • Stored lyric granules that contain cytotoxins
  • Cytotoxins are delivered directly onto the surface of the infected target cell
18
Q

?CTLs eliminate infected cells displaying peptide in Class I MHC Molecules

A
  1. Virus infects cell
  2. Viral proteins synthesized in cytosol
  3. Peptide fragments of viral proteins bound by MHC Class I in ER
  4. Bound peptides transported by MHC Class I to the cell surface
  • No co-stimulatory molecules are required for killing the target cell (binding of MHC I +TCR is ONLY thing needed)
  • Mechanisms —> granular proteins (granzymes (Activate caspases) and perforin (necessary for delivery of granzymes)
  • FasL and Fas (CD95)-controlled apoptosis ??
19
Q

CTL Killing: granzymes and perforin

A

Directional release of enzymes and targeted killing

  1. Ag recognition and binding of CTL to target cell
  2. CTL activation and granule exocytosis (perforin facilitates entry (like channels) of granzymes into the cytosol, granzymes activate apoptosis)
  3. Apoptosis of target cell
20
Q

CTL Killing: Fas/FasL

A

Whole point is to kill cells in neat and tidy way

Activated CTLs express FasL that binds to the death receptor Fas, which is expressed on many cell types. This interaction also results in activation caspases and apoptosis of Fas-expressing targets

  1. Fas/FasL mediated cell killing —> FasL on CTL interacts with Fas on target cell —> apoptosis of target cell
21
Q

CTL- A serial killer

A

There is a definite pattern in killing
-Ag specific recognition of peptide: MHC complexes on infected cells
Apoptosis
-prevents pathogen replication and release on infectious material
Production of IFNa/B
-INB replication of viruses (decreases protein synthesis)
-Increases expression of MHC class I on other infected cells

22
Q

Cooperation Exists between CD4 and CD8 T cell Subsets

A

Have phagocytose microbes in vesicles and cytosol —> CD4+ comes and binds, releases IFN-y —> viable microbe in cytosol (killing of microbes in phagolysosomes) —> CD8+ binds to infected cell —> killing of infected cell

23
Q

Mechanisms of NK Cell Killing

A
  • Kill tumor cells and virus infected cells
  • Kill by granzymes, perforin
  • Enhanced by IFN-a, IFN-B, and Is-12 (from Mo)
  • INB by MHC class I
  • CD116 and CD56 surface markers

Macrophage with phagocytose microbes release IL-12 —> NK cell released IFN-y —> killing of phagocytose microbes

24
Q

NK INB Receptor

A

Goes through and checks

  • Ligation of both activating and INB receptors on NK cell
  • Ligation of class I molecule with self-peptide with INB receptor on NK cell- no killing
  • Viral or other down regulation of expression of class I with self-peptide present leads to activated receptor only signaling
  • Cell death occurs by same mechanisms as CTLS (granzymes and perforin)

Basically what we learned before, without MHC class I presentation, NK cell will be activated

25
Q

Ab-Dependent Cell-Mediated Cytotoxicity (ADCC)

?

A

Another way to kill

  • NK cells, macrophages, monocytes, neutrophils, and eosinophils
  • Target recognition through IgE
  • Killing by lyric enzymes, TNF< and perforin

IgE is bound to Ag and Fc receptor —> release of granules

Fc??

26
Q

Memory T cells ?

A

-A naive T cell will be activated differentiate into effector cells and memory cells
-Most of the T cells become effector cells, which are short-lived (rest are memory, activated by Mo?)
-Memory CD4+ and CD8+ T cells require reactivating to regain their effector function
-Respond more rapidly than naive (spend more time in circulation)
-Can respond in peripheral tissues
-Require IL-7 (from B follicles)and IL-15 for survival
(Increase in regulation of anti-apoptic??)

Naiive T cells require survival signals from self MHC+self peptide —> Naive T cell encounters Ag -> Most activated T cells become effector cells —> many effector cells are short lived and die by apoptosis
—>Naive T cell encounters Ag —> some activated and/or effector cells become long lived memory cells—> IL-7 and IL-15 are required for survival —> Memory T cells can proliferate in response to elf MHC+self peptide

27
Q

Contraction of Immune Responses

A

Brings it to homeostasis

  • Number of specific close decrease as antigenic stimulus is removed
  • The majority of effector T lymphocytes will undergo apoptosis
  • A small percentage of the clones will become memory cells (express increased levels of anti-apoptotic protein, Bcl-2)

*Graph
Infection is over by about day 7, but day 14 T cell count back to “normal” and from there we get memory that can live ~30yrs

28
Q

Treg

A
  • CD4+ T cells
  • Constitutively express CTLA-4, CD-25 (aka IL-2aR) (increased affinity)
  • FOXp3 transcription factor
  • CTLA-4 binds B7 and shuts down IL-2 production (tells DC to stop showing Ag—> less activation)
  • Binds more avidly than CD28

When CTLA-4 binds to B7 it makes a costimulatory blockade

29
Q

Other Regulatory Receptors

A
  • CTLA-4 inductively on activated T cells (competes with CD28 for B7 binding)
  • PD-1 inductively on T cells, B cells, and myeloid cells

ITIM- INB (CTLA-4)
PD- INB (PD-1)

30
Q

CD4+ Th Cell Exhaustion

A

A. Acute infection
Effector T cells (T cell response) —> memory T cells: protective response to virus

B. Chronic Infection
Effector —> T cell response decrease —> Exhausted T cell: inability to respond to virus (PD-1, CTLA-4) (because of so much expression of PD and CTLA-4 cannot keep up)

31
Q

CD8+ CTL Exhaustion

A

Acute Infection -Ag cleared
Naive CD8+ T cell —> CD8+ CTL —> effector and memory CD8+ T cell —> cytokines

Chronic infection: Ag persists —> CD8 CTL —-> exhausted CD8+ T cell —> T cell exhaustion: no cytokine secretion, reduced proliferation, no target cell killing

32
Q

Evasion Mechanisms (virulence factors)

A

Mycobacteria- INB of phagolysosome fusion (survive in phagosome) — mycobacteria

Herpes simplex virus (HSV) - INB of Ag, interferes with TAP transporter
Cytomegalovirus- INB of Ag presentation, removal of class 1 MHC molecules from ER
Epstein-Barr virus (EBV)- INB of Ag, INB of proteasomal activity
—-INB of Ag presentation

Cytomegalovirus virus- production of IL-10, INB macrophage and DC activation
—-INB of macrophage activation

Pox virus- INB of effector cell activation, production of soluble cytokine receptors (secrete mimic cytokine receptor)
—-Block cytokine activation of effector cells

33
Q

Clinical Blue Box- Clare Bourbon

A

16yo, high fever, lost consciousness, red rash on arms and spread to body

HR- highly elevated
BP- very low

No signs of local infection

Using tampon, no sick contacts

WBC very elevated

Negative sepsis, vaginal infection
In shock —> BP so low

34
Q

Clinical Blue Box- Disease

A

TSS (Toxic Shock Syndrome)

  • Usually assoc. with localized S. Aureus infection, food poison, or local colonization
  • usually occurs in menstrating women
  • tampons provide food source for bacteria to multiple if kept in the vagina longer than recommended (story of Rely tampons)
35
Q

SuperAg activate T cells in the absence of co-receptors and co-stimulation

A

TSS is a superAg

  • SuperAg bind to the B chain of the TCR
  • Does not require Ag processing so very “fast” response
  • Activates T cells in the absence of cytokines and co-stimulators ligand binding
  • Polyclonal activation ~10-20% CD4+ T cells systemically vs.
  • “normal” Ag ~0.001-0.01T Cells systemically

CD4- secrete cytokines —> innate immunity —> SIRS —> shock (inflammatory cytokines)
CD8- kill stuff

36
Q

Common SuperAg

A

A lot of bacterial Ag that we know about

Most common superAg are bacterial products

There are several viral superAg as well although they are not as well elucidated

37
Q

Consequences of superAg Activation

A

-Fever, rash
-Edema, hypotension and shock with multiple organ failure due to intravascular volume depletion (into periphery due to TNF-a)
—TNF-a and IL-1 contribute to an increase in vascular permeability that leads to leakage of fluid from the intravascular space into the perivasculature

  • Have ligation of PAMPs/DAMPs to activate innate/inflammatory cytokines
  • Bacteria localized in vagina —> TSS protein traveling in blood

Trigger —> sterile causes —> SIRS —> severe SIRS —> Shock (hypotension)

Trigger —> infection (proven or suspected) —> sepsis —> severe sepsis —> septic shock

HDM Final (4 decks)

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