Cellular Immune Response & T Cell Activation

CELLULAR IMMUNE RESPONSE T CELL ACTIVATION ANN DONACHEY [email protected] WHATSAPP: 1-613-868-2284 SIGN IN FOR EACH SESSION YES, EVEN IF YOU’RE WATCHING THE RECORDING OR JUST DOING THE PRACTICE PROBS ENDOGENOUS ANTIGEN PROCESSING endogenous= antigen is inside the cell PROCESS: 1. protea...

CELLULAR IMMUNE RESPONSE T CELL ACTIVATION ANN DONACHEY [email protected] WHATSAPP: 1-613-868-2284 SIGN IN FOR EACH SESSION YES, EVEN IF YOU’RE WATCHING THE RECORDING OR JUST DOING THE PRACTICE PROBS ENDOGENOUS ANTIGEN PROCESSING endogenous= antigen is inside the cell PROCESS: 1. protease eats the antigen (which has been tagged by ubiquitin) into 8-10aa a. the other fragments are recycled into other proteins 2. Antigen fragment enters the ER via TAP dimer where they are shortened to the perfect length for the binding site (9 aa) 3. MHC1-peptide complex made inside ER 4. MHC1-peptide complex packaged into vesicle in golgi 5. vesicle fuses with membrane to express MHC1-peptide complex on cell surface 6. cytotoxic (CD8+) T cell responds WHO CAN DO THIS? -any nucleated cell -DC type 1 (cross priming: recall this is an exogenous antigen being processed like its endogenous) MHC 1 structure recap: -binding site: alpha1 and alpha 2 -transmembrane region: alpha 3 -wtf does beta do: “stabilize” aka nothing important BIG PICTURE: one cell can express 1 million MHCpeptide complexes about 200 MHCs connect with a single T cell at a time Exogenous ANTIGEN PROCESSING exogenous= antigen floating in the extracellular space PROCESS: 1. phagocytosis of exogenous antigen by DC cell, B cell or macrophage (APC) 2. Antigen broken down within its endosome into 13+amino acid fragments and waits 3. MHC2 assembled in the ER, and an invariant chain sits in the antigen binding site as a placeholder 4. MHC2 moved to golgi and packaged into a vesicle 5. MHC2 vesicle combined with antigen endosome to create MHC-peptide complex 6. MHC2-peptide complex put on the surface for helper T cell recognition WHO CAN DO THIS? -antigen presenting cell MHC 2 structure recap: -binding site: alpha1 and beta 1 -transmembrane region: alpha 2 and beta 2 NAIVE T CELL PRESENTATION immature DC located at common sites of entry of microbes they express receptors that let them capture microbes migrate to T cell rich zones in lymph nodes, where our naive T cells hangout mature DC cells express high levels of co-stimulatory molecules needed to activate naive T-cells NAIVE T CELL PRESENTATI ON LOVE THIS GRAPH PUTTING IT ALL TOGETHER 1. antigen capture Dendritic cells: located at sites of entry, express all the right receptors, capture antigen DC cells migrate to the T cell rich lymph nodes and spleen and mature along the way DC cells express co-stimulating molecules 2. mature DC presents to naive T cell require MHC-TCR and co-stimulation no co-stimulation=no response or tolerance 3. T cell activation T CELL ACTIVATION Activated T cells: secretes cytokines proliferation: increased by cloning the T cell differentiation: of proliferated activated T cells into effector and memory cells coat coat What are the effector T cells? CD4+: will coordinate with macrophages, B cells and DC cell close chitchatswhitmen CD8+: killing cell activation WHICH OF THE FOLLOWING IS AN ACTIVATING CO-STIMULATORY MOLECULE FOR T CELLS? A) CTLA B) PD-1 C) CD3 D) CD28 AnaBT 00154 WHICH OF THE FOLLOWING IS AN ACTIVATING CO-STIMULATORY MOLECULE FOR T CELLS? A) CTLA B) PD-1 C) CD3 D) CD28 WHAT IS THE RESULT OF A LACK OF COSTIMULATORY MOLECULES WHEN TRYING TO ACTIVATE T CELLS? A) APOPTOSIS B) SELECTION C) ANERGY D) TRANSDUCTION WHAT IS THE RESULT OF A LACK OF COSTIMULATORY MOLECULES WHEN TRYING TO ACTIVATE T CELLS? A) APOPTOSIS B) SELECTION C) ANERGY D) TRANSDUCTION T CELL ACTIVATION two factor authentication system: we don’t want accidental killing TWO SIGNAL SYSTEM: signal 1: recognition of antigen by MHC-TCR interaction with a legit peptide antigen and a stabilizing C3 complex signal 2: co-stimulatory molecule that either enhances or inhibits the action of the T cell. CO-STIMULATORS Activating receptors: APC has the B7 : T cell has the CD28 activates naive T cells promote survival promote proliferation promote differentiation increase of IL-2 receptor expression and IL-2 secretion ICOS: ICOS-L critical for helper T cell-dependent antibody response Inhibitory receptors: CTLA-4 : B7 inhibits the initial activation of T cells in secondary lymphoid organs potential for therapy, we can add soluble CTLA so it inhibits T cells from inducing rheumatoid arthritis and transplant rejection related inflammation PD-1 : PD-L inhibits the activation of effector T cells in peripheral tissues CO-STIMULATORS CD40-CD40L CD40 on APC CD40-L on T cell doesn’t directly enhance T cell activation BUT enhances their response by activating APCs basically, if B7 and CD28 are not connecting, CD40 and CD40L can be like....go so we can get this started. inhibitors of CD40 in clinical trials for transplant rejection and chronic inflammatory disease THERAPEUTIC APPLICATION Hereally likesthese CD40-CD40L inhibitors in clinical trials for transplant rejection and chronic inflammatory disease CTLA-4-Ig therapy approved for therapy of rheumatoid athritis and transplant rejection in clinical trials for treatment of psoriasis and Crohn’s disease CTLA-4 and PD-1 inhibiting antibodies trials for tumor immunotherapy WHAT HAPPENS WHEN WE ACTIVATE T CELLS increased expression of surface molecules IL-2 secretion and IL-2Ra reception IL-2Ra turns into IL-2Raby (high affinity) growth, survival and differentiation factor produced mainly by CD4+ T cells early after stimulation to increase production of IFN-y and IL-4 acts in an autocrine or paracrine manner IL-2 fast facts: clonal expansion growth, survival and production of daughter cells from single cell differentiation factor for T-cells Produced mainly by CD4 T cells all daughters have the same antigen specificity acts autocrine or paracrine T regulatory cells sequester it WHAT HAPPENS WHEN WE ACTIVATE T CELLS post-activation: huuuge population increase a happen again Thutmose preactivation: low level contraction: new baseline of resting cells, not as low as before activation, but not ashigh as midantigen fight CD4+: the helper T cells Th1 Th2 Th17 THE EFFECTOR CELLS CD8+: cytotoxic killer cells Memory T cells: linear pathway: naive cells, become effector T cells, and then retire to memory T cells divergent pathway: naive cells become memory T cells function to prolong survival by expressing anti-apoptotic proteins BCL-2 and BCL-X use IL-7 to proliferate at a slow burn to maintain pop and only replicate enough to self-renew rapid antigen response: will reactivate when in contact with antigens faster than we can stimulate naive cells ability to migrate to peripheral tissues to respond to antigens Decline of immune response: elimination of antigen maintain homeostasis decline due to; no co-stimulation decrease growth factor production (IL-2) activation of sensors of cellular stress no T cell apoptosis What is the function of CD40-CD40L? a) to directly enhance T cell activation b) it is inhibitory co-stimulator c) causes clonal anergy d) enhances expression of activating co-stimulator What is the function of CD40-CD40L? a) to directly enhance T cell activation b) it is inhibitory co-stimulator c) causes clonal anergy d) enhances expression of activating co-stimulator HELPER T CELLS HELPER T CELLS learnthe FUNCTION THROUGH chart CYTOKINE SECRETION play central role in immune response Th cells are involved in cellular, humoral and inflammatory responses divided into subsets according to cytokines they produce differentiation into subsets is called polarization induction stable commitment amplification LOVE THIS CHART TH1 POLARIZATION induced by microbes CENTRAL ELEMENT OF CELLULAR IMMUNITY induced by: DCs, macrophages and NK cells triggered by: IL-12 and IFNy function: mediated by IFN-y activates macrophages to phagocytose stimulate IgG production IFN-Y activates macrophages promotes IgG class switching, inhibits IgETara.sk beswymdgftontf about amplifies Th1 subset and inhibits the development of Th2 and Th17 stimulates expression of molecules to enhanve MHC 1 and 2 therapeutic applications: atopic dermatitis astrocytoma treatment fibrosarcoma treatment brain tumor treatment TH2 POLARIZATION triggered by DC type 2 induced by: helminthic infections (extracellular antigens) induced by: DC cells, mast cells and eosinophils triggered by: IL-4 and IL-1 function: mediated by IL-4, IL-5, IL-10 and IL-13 enhances B cell proliferation and Ig secretion of IgE cause mast cell and eosinophil degranulation increase peristalsis activate alternative macrophages recall: type 1 hypersensitivity pathway FUNCTIONS OF IL-4, IL-5 AND IL-13 IL-4 acts on B cells: to cause IgE antibody release induces mast cell degranulation IL-4 and IL-13 acts on intestinal mucosa to induce peristalsis IL-4 and IL-13 activates alternative M2 macrophages IL-5 induces eosinophil degranulation ACTIVATED BY TH1 ACTIVATED BY TH2 accommodation Fatiewing Time toheal TH17 POLARIZATION induced by: extracellular bacteria and fungi these triggered by: IL-1 and IL-6 (pro-inflam Tyremember cytokines) function: mediated by IL-17 and IL22 7417 IS secreatedby function maintained by IL-23 NOTsecreated Then by function: leukocytes (neutrophils) inflammation induction epithelial cells increase barrier integrity both cause production of antimicrobial peptides WHICH OF THE FOLLOWING TARGETS EOSINOPHIL ACTIVATION? A) CD8 B) TH2 C) TH1 D) TH17 WHICH OF THE FOLLOWING TARGETS EOSINOPHIL ACTIVATION? A) CD8 B) TH2 C) TH1 D) TH17 A PARASITE HAS INVADED CARROT, THE PONY, AFTER SHE TOOK A LONG SWIM IN A DIRTY RIVER. HER EOSINOPHILS WERE LIKELY ACTIVATED BY WHICH OF THE FOLLOWING CYTOKINES? A) IFNY B) TGFB C) TH1 D) IL-4 A PARASITE HAS INVADED CARROT, THE PONY, AFTER SHE TOOK A LONG SWIM IN A DIRTY RIVER. HER EOSINOPHILS WERE LIKELY ACTIVATED BY WHICH OF THE FOLLOWING CYTOKINES? A) IFNY B) TGFB C) TH1 D) IL-4 POLARIZATION OF THE FOLLOWING CELL IS CENTRAL TO THE ELEMENT OF CELLULAR IMMUNITY? A) TH2 B) M2 C) TH17 D) TH1 POLARIZATION OF THE FOLLOWING CELL IS CENTRAL TO THE ELEMENT OF CELLULAR IMMUNITY? A) TH2 B) M2 C) TH17 D) TH1 WHICH OF THE FOLLOWING ACTIVATES TH1 POLARIZATION? A) IL-4 AND IL-5 B) IFN-Y AND IL-17 C) IL-12 AND IFN-Y D) TGFB AND M2 WHICH OF THE FOLLOWING ACTIVATES TH1 POLARIZATION? A) IL-4 AND IL-5 B) IFN-Y AND IL-17 C) IL-12 AND IFN-Y D) TGFB AND M2 M2 MACROPHAGES ARE...? A) INDUCED BY TH2 B) ACTIVATED BY IL-13 AND IL-4 C) CAUSE WOUND REPAIR D) ALL OF THE ABOVE E) NONE OF THE ABOVE, THEY ARE CLASSICALLY ACTIVATED M2 MACROPHAGES ARE...? A) INDUCED BY TH2 B) ACTIVATED BY IL-13 AND IL-4 C) CAUSE WOUND REPAIR D) ALL OF THE ABOVE E) NONE OF THE ABOVE, THEY ARE CLASSICALLY ACTIVATED CYTOTOXIC T CELLS CD8 DIFFERENTIATION frens if CD8orcD4 Naive T cells DO NOT present cytotoxic activity or secrete IFN-y activation requires DC and cross-priming on MHC1 sometimes require helper T cells to support the differentiation of naive to active most helpful for latent viral infections, organ transplants and tumors or weak immune response sometimes they directly stimulate CD8 differentiation with cytokines sometimes they enhance APC to stimulate CD8 differentiation Differentiation gives them to the tools to kill: lysosomes with perforin and granzyme capability to secrete cytokines, mostly IFN-y Controlled by transcription factor T-bet and Eomesodermin IFN-Y PRODUCING CELLS CD8 FUNCTION kill virally infected cells kill tumor cells produce cytokines acute graft rejection INSTA REEL- NOT A RELIABE RESOURCE- BUT FUNNY CD8 RELEVANT CYTOKINES IL-2: proliferation and differentiation of of CD8+ into CTLs and memory CTLs IL-12 and type 1 IFN: differentiation of naive T cells into effector CTLs IL-15: survival of memory CD8 T cells IL-21: induces CD8 memory T cells formation CD8 FUNCTION eliminate intracellular microbes VIRUSES triggers apoptosis of infected cells mediated by; intracellular adhesion moleule ICAM and LFA integrin locks the two cells together releases 2 types of cytotoxic proteins perforin (punches holes) and granzyme B: activates caspase pathway and triggers apoptosis death receptor: Fas (on CD8)-FasL (target cell) causing apoptosis secreted IFN-y classical macrophage activation stimulates hypersensitvity reactions T CELL EXHAUSTION chronic infection gradually extinguish caused by reduced production of IFN-y and increase expression of inhibitory receptors (CTLA and PD-1) TRUE OR FALSE: THE PRIMARY FUNCTION OF CYTOTOXIC T LYMPHOCYTES IS TO HELP ACTIVATE OTHER IMMUNE CELLS TRUE OR FALSE: THE PRIMARY FUNCTION OF CYTOTOXIC T LYMPHOCYTES IS TO HELP ACTIVATE OTHER IMMUNE CELLS MATCH THE CELL TO THE MAIN CYTOKINE THEY SECRETE CTL TH1 TH2 TH17 IL-4 IFN-Y IL-17 IL-13 MATCH THE CELL TO THE MAIN CYTOKINE THEY SECRETE CTL TH1 TH2 TH17 IL-4 IFN-Y IL-17 IL-13 THE OUTCOME OF CD8 T CELLS IS? A) PERFORIN GRANZYME B) DEATH RECEPTOR ACTIVATION C) CASPASE ACTIVATION D) ALL OF THE ABOVE THE OUTCOME OF CD8 T CELLS IS? A) PERFORIN GRANZYME B) DEATH RECEPTOR ACTIVATION C) CASPASE ACTIVATION D) ALL OF THE ABOVE TRUE OR FALSE: CYTOKINES HAVE HIGH AFFINITY FOR THEIR RECEPTORS AND ONLY ACT IN AN ENDOCRINE MANNER TRUE OR FALSE: CYTOKINES HAVE HIGH AFFINITY FOR THEIR RECEPTORS AND ONLY ACT IN AN ENDOCRINE MANNER A Hormones only endocrine cytokines_Endocrine paracrine autocrine THE ACTION OF ONE CYTOKINE INHIBITING THE EFFECT OF ANOTHER IS AN EXAMPLE OF A) SYNERGISM B) ANTAGONISM C) PLEITROPISM D) AGONISM THE ACTION OF ONE CYTOKINE INHIBITING THE EFFECT OF ANOTHER IS AN EXAMPLE OF A) SYNERGISM B) ANTAGONISM C) PLEITROPISM D) AGONISM Ignore YOU ARE ARTIFICALLY ASSEMBLING A TH2 MOLECULE, WHICH IS CORRECT IN THAT PROCESS? A) VDJ ASSEMBLES IN BETA CHAIN BEFORE VDJ ASSEMBLES IN THE ALPHA CHAIN B) ALPHA CHAIN ASSEMBLES IS VJ REGION BEFORE VDJ ASSEMBLES IN THE BETA CHAIN C) VDJ ASSEMBLES IN THE BETA CHAIN BEFORE VJ ASSEMBLES INT HE ALPHA CHAIN D) TH2 ONLY HAS GAMMA-DELTA TCRS YOU ARE ARTIFICALLY ASSEMBLING A TH2 MOLECULE, WHICH IS CORRECT IN THAT PROCESS? A) VDJ ASSEMBLES IN BETA CHAIN BEFORE VDJ ASSEMBLES IN THE ALPHA CHAIN B) ALPHA CHAIN ASSEMBLES IS VJ REGION BEFORE VDJ ASSEMBLES IN THE BETA CHAIN C) VDJ ASSEMBLES IN THE BETA CHAIN BEFORE VJ ASSEMBLES INT HE ALPHA CHAIN D) TH2 ONLY HAS GAMMA-DELTA TCRS THANK YOU! GOODLUCK