Cell Immune Response Flashcards
Clinical case.
‘Yescarta’
-treat adults w lg B cell lymphoma
-CAR T cells = genetically engineered T cells w chimeric antigen receptor
Describe antigen presentation to naive T cells.
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
Describe the properties of DCs that make them the most effective APCs for initiating primary T cell responses.
- At common sites of entry of microbes
- Express receptors to capture & respond to microbes
- Migrate to T cell rich zones of LN where naive T cells are
- Mature DCs express high level of co stim
- Ingest infected/tumor cells & present antigens to CD8 T cells
Describe the activation of T cells.
-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
Describe the 1st signal for T lymphocyte activation.
-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
Describe the 2nd signal for T lymphocyte activation.
-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
Describe the role of CD40 in T cell activation.
-enhance T cell resp by activating APCs
(Inhibitors of CD40 pathway for transplant rejection & chronic inflammatory diseases)
Describe the regulation of T cell activation.
-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)
Describe the interactions in regulation of T cell activation.
- CD28 =
-activate native T cells via costim
-generation of regulatory T cells - ICOS:ICOS-ligand =
-imp for helper T cell dependent antibody resp
-costim of effector & regulatory T cells
-generation of follicular helper T cells - CTLA-4:B7 =
-inhibit initial activation of T cells in secondary lymphoid organs
-neg regulation of immune response (self tolerance) - PD1:PD-ligand =
-inhibit activation of effector cells in peripheral tissue
-neg regulation of T cells
-express both T & B cells
Describe therapeutic costimulatory blockade.
- CTLA-4-lg =
-approved for rheumatoid arthritis & transplant rejection
-clinical trial for treatment of psoriasis & Crohn’s disease - CD40 inhibitors =
-clinical trial for transplant rejection & chronic inflammatory diseases - Antibodies against CTLA-4 & PD-1 for immunotherapy of tumors
Describe the functional responses of T cell activation.
- Increase in surface molecule expression
- IL2 secretion & IL2Ra expression
- Clonal expansion of T cells
Describe an increase in surface molecule expression.
-CD69
-CD25 (IL2Ra)
-CD40L
-CTLA4
-adhesion molecules
-chemokine receptors
Describe IL2 secretion & IL2Ra expression.
-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
Describe the functions of IL2.
-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)
Describe clonal expansion of T cells.
-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
Describe the differentiation of activated T cells into effector cells.
-effector CD4 cells = express surface molecules & secrete cytokines that activate other cells (APCs)
-effector CD8 cells = cytotoxic
Describe the development of memory T cells.
-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)
Describe the properties of memory T cells.
-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
Describe the decline of T cell responses.
-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
Describe the role of CD4 T cells in eradicating infections.
Describe what T cell responses involve.
- Initial activation in lymphoid organs
- Generation of effector & memory cells
- Migration of effector cells to sites of infection
- Elimination of infectious pathogens at sites
- Functions of CD4 T cells mediated by cytokines
- CD4 effector T cells classified according to cytokines they make
Describe the subsets of CD4 effector T cells.
Describe the development of TH1, TH2, TH17 subsets.
-develop from naive CD4 T lymphocytes
-‘polarization’ of T cells
-process:
>induction
>stable commitment
>amplification
Describe the TH1 subset.
-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
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)
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
Describe TH1 mediated classical macrophage activation.
-TH1 cells activate macrophages by contact mediated signals delivered by CD40L & IFNY
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
Describe classical VS alternative macrophage activation.
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
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
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
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
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
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
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
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
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
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
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
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)
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)
Describe examples of chronic viral infections in animals.
-feline viral rhinotracheitis
-feline calcivirus
-canine distemper
-feline leukemia
