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JOURNAL CLUB, 28th september 2007

JOURNAL CLUB, 28th september 2007. T-CELL ACTIVATION. T-CELLS ARE ABLE TO DISTINGUISH BETWEEN SELF AND NON SELF ANTIGENS (Ag) T-CELL RECEPTOR (TCR) PLAY AN IMPORTANT ROLE, BECAUSE IT RECOGNIZES Ag PRESENTED BY APC IN MHC AND THIS LEADS TO THE

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JOURNAL CLUB, 28th september 2007

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  1. JOURNAL CLUB, 28th september 2007

  2. T-CELL ACTIVATION • T-CELLS ARE ABLE TO DISTINGUISH BETWEEN SELF AND NON SELF • ANTIGENS (Ag) • T-CELL RECEPTOR (TCR) PLAY AN IMPORTANT ROLE, BECAUSE IT • RECOGNIZES Ag PRESENTED BY APC IN MHC AND THIS LEADS TO THE • INDUCTION OF INTRACELLULAR SIGNALING AND T-CELL RESPONSES • T-CELLS RESPONSIVENESS AND TCR SIGNALING VARY WITH T-CELL • DEVELOPMENT • miRNA WERE RECENTLY DISCOVERED TO BE DIFFERENTIALLY EXPRESSD DURING HEMATOPOIETIC DIFFRENTIATION AND THEY MAY BE INVOLVED IN CONTROLLING THE DEVELOPMENT OF IMMUNE SYSTEM

  3. IMMATURE T-CELLS DN1 (CD44+, CD25-) DN2 (CD44+, CD25+) DN3 (CD44-, CD25+) DN4 (CD44-, CD25-) ORDER OF APPEREANCE DURING DEVELOPMENT DN (CD4-, CD8-) SP (CD4-, CD8+) (CD4+, CD8-) DP (CD4+, CD8+) RESULTS DINAMIC REGULATION OF miR181a EXPRESSION IN T-CELLS MATURATION

  4. miR181a EXPRESSION AUGMENTS TCR SIGNALING • TO ACCESS HOW miR181a AFFECTS TCR SIGNALING: • INCREASED EXPRESSION OF miR181a IN 5C.C7 • Ag PRIMED CD4+ T-CELLS • STIMULATED WITH MCC (AGONIST); TCR SIGNALING • STRENGHT ASSESSED BY MESASURING Ca2+INCREASE HIGH LEVEL OF miR181a AUGMENTS TCR-MEDIATED T-CELLS ACTIVATION

  5. miR181a EXPRESSION AUGMENTS TCR SIGNALING TCR SIGNAL INPUT=NUMB OF ANTIGENIC pMHC COMPL. AT T:APC INTERFACE TCR SIGNAL OUTPUT=CALCIUM CONCENTR CHANGES IN CYTOSOL miR181a EXPRESSION INCREASES T CELLS SENSITIVITY

  6. miR181a CONVERTS ANTAGONIST INTO AGONIST • MCC99R INDUCE CALCIUM INCREASE IN miR181a CELLS • MCC99R ALONE STIMULATE EFFECTOR T-CELLS FUNCTION

  7. miR181a EXPRESSION DOESN’T ALTER CD4 AND TCR DENSITY ON T-CELLS • SURFACE • WHEN CD28 IS BLOCKED AND miR181aT-CELLS ARE TRETAED WITH MC99R, • THEY CAN STILL RESPOND TO THE ANTAGONIST. • miR181a MODULATE TCR SENSITIVITY BY CONTROLLING INTRACELLULAR • SIGNALING MOLECULES, SUCH AS SHP1 (Lck NEGATIVE REGULATOR) • AND ERK1/2 PATHWAYS • USINGUNPUBLISHED COMPUTER PROGRAMS, THEY FOUND TARGETS FOR mir181a: • Lck-SPECIFIC-TYROSIN POHOSPHATASE, SHP-2 AND PTPN22 • ERK-SPECIFIC-PHOSPHATASE, DUSP5 AND DUSP6

  8. miR181a REPRESSES MULTIPLE PHOSPHATASE IN T-CELLS

  9. miRNA181a INCREASES THE BASAL PHOSPHORILATION LEVELS OF Lck AND ERK miR181a EXPRESSION INHIBITS Lck/SHP1 INTERACTION

  10. MECHANISM OF TCR SIGNALING

  11. MULTITARGET REPRESSION IS REQUIRED FOR miR181a FUNCTION IN TCR SIGNALING EFFICACY AND SPECIFICITY OF shRNA CONSTRUCTS STRENGHT OF Ca2+ RESPONSE AND % OF T-CELLS ACTIVATED

  12. CONTRIBUTION OF EACH PHOSPHATASE TO Ag DISCRIMINATION

  13. miR181a MODULATES NEGATIVE AND POSITIVE SELECTION OF T-CELLS TREATMENT WITH ANTAGOMIR RESTORED PHOSPHATASE/KINASE INVOLVED IN TCR SIGNALING IN DP CELLS INHIBITION OF ERK ACTIVITY

  14. CONCLUSIONS • miRNAs ARE A NEW CLASS OF REGULATORY • MOLECULES IN THE IMMUNE SYSTEM • miR181a IS AN INTRINSIC MODULATOR • OF TCR SENSITIVITY IN T-CELL DEVELOPMENT • (ALTHOUGH OTHER COMPONENTS MAY CONTRIBUTE TO • THESE CHANGES IN SENSITIVITY) • miRNAs CAN MODULATE MULTIPLE TARGETS • AS THEY EXERT A QUANTITATIVE REGULATION • THAT ALLOWS A DISCRIMINATIVE SWITHC IN • Ag RECOGNITION

  15. Paper discussion • What is the key experiment? (the one confirming the statement in the title) • What is the strongest point? • What is the weakest point? and What to do to strenghten it? • What is the take home message? (summarize it in a sentence)

  16. • NEGATIVE • Any cell that reacts strongly to self antigen is deleted • POSITIVE •Any cell that doesn’t recognize self MHC is deleted • Ensures functional matching of receptor, co-receptor and class of MHC •Lineage commitment

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