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Cell Immune Response Flashcards

1
Q

Clinical case.

A

‘Yescarta’
-treat adults w lg B cell lymphoma
-CAR T cells = genetically engineered T cells w chimeric antigen receptor

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2
Q

Describe antigen presentation to naive T cells.

A

role of DC in initiating T cell responses
-T cell resp initiated in peripheral lymphoid organs where protein antigens are transported after being collected from portal of entry
-DC resident in epi & tissues = capture protein antigens & transport to draining LN

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3
Q

Describe the properties of DCs that make them the most effective APCs for initiating primary T cell responses.

A
  1. At common sites of entry of microbes
  2. Express receptors to capture & respond to microbes
  3. Migrate to T cell rich zones of LN where naive T cells are
  4. Mature DCs express high level of co stim
  5. Ingest infected/tumor cells & present antigens to CD8 T cells
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4
Q

Describe the activation of T cells.

A

-naive T cells circulate in secondary lymphoid organs
>functional only after activated
-antigen recog by T cells leads to activation in form of:
1. Cytokine secretion
2. Proliferation - increase in # of T cells of specific clone
3. Differentiation of naive cells into effector & memory T cells

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5
Q

Describe the 1st signal for T lymphocyte activation.

A

-recog of antigen = 1st signal for activation of T cells
-CD4 & CD8 T cells recognize peptide MHC complex on APC
-other T cell surface proteins participate in process of T cell activation

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6
Q

Describe the 2nd signal for T lymphocyte activation.

A

-costimulation
-functions together w antigen (signal 1) to stimulate T cells
-signal 2 = CD28:B7 works w antigen recog to promote survival, proliferation, & differentiation of T cells
>imp for initiating resp by activating naive T cells

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7
Q

Describe the role of CD40 in T cell activation.

A

-enhance T cell resp by activating APCs
(Inhibitors of CD40 pathway for transplant rejection & chronic inflammatory diseases)

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8
Q

Describe the regulation of T cell activation.

A

-T cell regulation influenced by activating & inhibitory receptors of CD28 fam
-inhibitory receptor of CD28 =
>CTLA-4 (cytotoxic T lymphocyte antigen 4)
>PD-1 (programmed death 1)

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9
Q

Describe the interactions in regulation of T cell activation.

A
  1. CD28 =
    -activate native T cells via costim
    -generation of regulatory T cells
  2. ICOS:ICOS-ligand =
    -imp for helper T cell dependent antibody resp
    -costim of effector & regulatory T cells
    -generation of follicular helper T cells
  3. CTLA-4:B7 =
    -inhibit initial activation of T cells in secondary lymphoid organs
    -neg regulation of immune response (self tolerance)
  4. PD1:PD-ligand =
    -inhibit activation of effector cells in peripheral tissue
    -neg regulation of T cells
    -express both T & B cells
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10
Q

Describe therapeutic costimulatory blockade.

A
  1. CTLA-4-lg =
    -approved for rheumatoid arthritis & transplant rejection
    -clinical trial for treatment of psoriasis & Crohn’s disease
  2. CD40 inhibitors =
    -clinical trial for transplant rejection & chronic inflammatory diseases
  3. Antibodies against CTLA-4 & PD-1 for immunotherapy of tumors
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11
Q

Describe the functional responses of T cell activation.

A
  1. Increase in surface molecule expression
  2. IL2 secretion & IL2Ra expression
  3. Clonal expansion of T cells
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12
Q

Describe an increase in surface molecule expression.

A

-CD69
-CD25 (IL2Ra)
-CD40L
-CTLA4
-adhesion molecules
-chemokine receptors

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13
Q

Describe IL2 secretion & IL2Ra expression.

A

-IL2 is a growth, survival, & differentiation factor for T cells
-made by CD4 T cells after antigen recog & costim
-acts on same/adjacent cells that make it

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14
Q

Describe the functions of IL2.

A

-stimulate survival, proliferation, & differentiation of antigen activated T cells
-increase production of IFN-y & IL4 by T cells
-required for survival & function of regulatory T cells
*therapeutic use: cancer, sarcomas (canary pox virus as a vector to activate CD8 T cells)

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15
Q

Describe clonal expansion of T cells.

A

-proliferation results in increase in # of antigen specific clones
-make daughter cells from a single cell = share same antigen specificity
-before antigen exposure the freq of naive T cells specific for any antigen is 1 in 10^5 T cells
-after antigen exposure the freq of CD8 T cells increases to 1 in 3 CD8 T cells & 1 in 100 CD4 T cells

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16
Q

Describe the differentiation of activated T cells into effector cells.

A

-effector CD4 cells = express surface molecules & secrete cytokines that activate other cells (APCs)
-effector CD8 cells = cytotoxic

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17
Q

Describe the development of memory T cells.

A

-T cell mediated immune resp to antigen = gen of memory T cells specific for that antigen
-persist for years
-develop from:
>effector cells in linear pathway
>effector pop in divergent differentiation (no effector phase)

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18
Q

Describe the properties of memory T cells.

A

-increased expression of antiapoptotic proteins (Bcl-2 & Bcl-X1) = resp for prolonged survival (long-lived cells)
-respond more rapidly to antigen stimulation than naive cells specific for same antigen
-# of memory T cells specific for antigen is greater than the # of naive cells specific for same antigen
-migrate to peripheral tissues & respond to antigens at those sites
-slow proliferation in absence of antigen = self renewal for prolonged life span
-maintenance of memory cells dependent on cytokines (IL7) -> doesnt require antigen recognition

19
Q

Describe the decline of T cell responses.

A

-elimination of antigen = contract T cell response
-maintain homeostasis in immune system
-decline due to:
>cessation of co stim
>cessation of growth factor production (IL2)
>activate sensors of cellular stress (BH3/Bim) which triggers apoptosis of T cells

20
Q

Describe the role of CD4 T cells in eradicating infections.

21
Q

Describe what T cell responses involve.

A
  1. Initial activation in lymphoid organs
  2. Generation of effector & memory cells
  3. Migration of effector cells to sites of infection
  4. Elimination of infectious pathogens at sites
  5. Functions of CD4 T cells mediated by cytokines
  6. CD4 effector T cells classified according to cytokines they make
22
Q

Describe the subsets of CD4 effector T cells.

23
Q

Describe the development of TH1, TH2, TH17 subsets.

A

-develop from naive CD4 T lymphocytes
-‘polarization’ of T cells
-process:
>induction
>stable commitment
>amplification

24
Q

Describe the TH1 subset.

A

-induced by microbes ingested by phagocytes & by microbes that activate phagocytes
-major effector T cell pop in phagocyte mediated host defense
-central reaction of cell mediated immunity
DEVELOPMENT
-TH1 differentiate in presence of IL12 & IFNY made by APCs
-IFNY & IL12 stimulate TH1 differentiation by activating transcription factors: T-bet, STAT1, STAT2
FUNCTIONS
-activate macrophages to ingest & destroy microbes
-TH1 or follicular helper T cells stimulate production of IgG antibodies
-effector functions of TH1 cells mediated thru IFNY

25
Describe why IFNy is imp for TH1 cells.
‘Type II interferon’ -activates macrophages -acts on B cells to promote IG2a subclass switching & inhibits switching to IgE -IFNy amplifies TH1 subset & inhibits development of TH2 & TH17 -stimulates expression of molecules that enhance antigen presentation (EX: MHC I & II)
26
Describe the therapeutic use of IFNY in vet med.
-recombinant K9 IFNy = atopic dermatitis -hIFNy against K9 astrocytoma -fIFNY in combo w fIL2 & fGM-CSF for fibrosarcoma -IFNy gene therapy in K9 brain tumors
27
Describe TH1 mediated classical macrophage activation.
-TH1 cells activate macrophages by contact mediated signals delivered by CD40L & IFNY
28
Describe the TH2 subset.
-TH2 subset mediates phagocyte-independent defense -eosinophils & mast cells -imp for helminthic infections -central to development of allergic diseases -TH2 differentiation by IL4 in response to helminths/allergens -IL4, IL5, IL13 = main TH2 cytokines -stimulate: >production of IgE >mast cells >eosinophils (elim helminthic infections) >alternative macrophage activation
29
Describe classical VS alternative macrophage activation.
30
Describe the TH17 subset.
-recruit leukocytes & inflammation -destroy extracellular bacteria & fungi -stimulated by pro inflammatory cytokines in response to bacteria/fungi -IL1 & IL6 initiate TH17 differentiation -IL23 maintains proliferation & differentiation of TH17 FUNCTIONS: >combat microbes by recruiting neutrophils to site >make IL17 = induce neutrophil rich inflammation & production of antimicrobial substances
31
Describe the elimination of viruses by the immune system.
-viruses cant be destroyed by cells that lack microbial mechanisms or in theyre in cytosol -KILL INFECTED CELL
32
Describe the main functions of CD8 T cells.
-kill cells w virus in cytosol mediated by CD8 cytotoxic T lymphocytes (CTL) *other functions -eradication of tumors -cytokine production -acute rejection of organ allografts
33
Describe the CD8 T cell CTL machinery to kill.
Machinery to kill target cells: 1) modified lysosomes - granules that have perforin & granzymes 2) capability to secrete cytokines, IFNy *differentiation by T-bet & oesmodermin
34
Describe the antigens for activation of CD8 T cells.
-cytosol derived antigens stimulate CD8 T cells -naive CD8 T cells recog antigen presented by MHC class I on dendritic cells -some APCs arent infected by virus & dont endogenously synthesize viral antigen >cross presentation (only special APCs like CD8 DCs) >present tumor antigens
35
Describe the role of helper T cells in CD8 T cell differentiation.
-naive CD8 T cells may require CD4 T cells to help differentiate into functional CTLs & memory cells >if APCs directly infected by microbe, CD4 T cell help is not critical >CD4 helper T cells required for CD8 T cell responses to: latent viral infections, organ transplants, tumors -weak innate immune reactions CD4 T cell help required
36
Describe the mechanisms of CD4 T cell help to CD8 CTLs differentiation.
1) CD4 helper T cells make cytokines to stimulate CTL differentiation 2) CD4 helper T cells enhance ability of APCs to stimulate CTL differentiation
37
Describe the role of cytokines.
1) IL12 & type I IFNs = stimulate differentiation of naive CD8 T cells into effector cells 2) IL2 = promotes prolif & differentiation of CD8 T cells into effector CTLs & memory CTLs 3) IL21 = make activated CD4 T cells that induce CD8 T cell memory 4) IL15 imp for survival of memory CD8 T cells
38
Describe the effector functions of CD8 cytotoxic T cells.
1) CD8 CTLs eliminate intracellular microbes by killing infected cells 2) CD8 T cells secrete IFNy >contribute to classical macrophage activation in host defense >stim hypersensitivity reactions
39
Describe the mechanisms of CTL-mediated cytotoxicity.
-recog of target cells & delivery of proteins that induce cell death *process: >antigen recog >activate CTLs >delivery of lethal hit that kill target cells >release CTLs
40
Describe the recognition of antigen & activation of CTLs.
-efficiently recog by CTLs target cells must: >express class I MHC molecules complexed to a peptide >bind to the CD8 coreceptor >bind intracellular adhesion molecule 1 >form immunological synapse
41
Describe the 2 killing pathways.
1) major cytotoxic proteins in the granules of CTLs (& NK cells) = granzyme B & perforin 2) CTLs express membrane protein called Fas ligand (FasL) = bind to death receptor Fas (expressed on many cells)
42
Describe the inhibition of CD8 T cells responses: T cell exhaustion.
-chronic viral infections = responses of CD8 T cells initiated but gradually extinguished = 'exhaustion' -due to: >reduced production of IFNy >increased expression of multiple inhibitory receptors (PD1)
43
Describe examples of chronic viral infections in animals.
-feline viral rhinotracheitis -feline calcivirus -canine distemper -feline leukemia

Immuno (24 decks)

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