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TCR Signaling and T Cell Development

44:48 recording · AUTO · 2 speakers

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Brief overview

Leslie Berg traces molecular biology to TCR signaling, arguing signal strength should reshape CAR T cells.

  1. The people around you redirect your questionsA kinase colleague at Harvard turned a thymic selection researcher into a signaling researcher, and Berg tells junior faculty they will be doing completely different things within a year or two.
  2. Unexpected results are where learning happensIf every experiment turned out as predicted, she says, we would already know everything; a sound experiment teaches you something whether or not you like the answer.
  3. One CAR cannot make effectors and memorySince 95% of kids respond but only half hold that response past a year, she proposes splitting the transduced cells between constructs with different signaling domains.
Executive Summary AI
  • Cindy Leifer records this Immune booster at the American Association of Immunologists conference in Honolulu with Leslie Berg, professor and chair at the University of Colorado School of Medicine, former AAI president and co-first editor-in-chief of ImmunoHorizons.0:53
  • Berg describes a molecular biology PhD at UC Berkeley on bovine papillomavirus, an 8KB circular DNA virus that transformed cells, before deciding with no immunology coursework to join Mark Davis' lab at Stanford, which grew from nobody to 25 people in three years while she made the TCR transgenic mice used to test positive and negative selection.3:47
  • Her first faculty job was a basic cell and molecular biology department at Harvard, chosen deliberately to avoid aggressive senior people who wanted to take her project over; a colleague down the hall who had shown SRC was a tyrosine kinase pushed her to screen for new T cell kinases beyond LCK, and after seven years she moved to the University of Massachusetts Medical School, where immunologist c8:27
  • She names her PhD advisor Mike Botchin as the biggest influence, for treating everyone who would talk science as a contributor and for dropping any hypothesis the data contradicted, and she carries that into a lab where students must be independent and where an unexpected but well-controlled result is the one that teaches something.18:06
  • Her open question is still how TCR signal strength wires different fates, which she ties to CAR T cells: 95% of pediatric ALL patients respond and only 50% still respond after more than a year, so she argues one CAR cannot make both effector and memory cells, and her advice for this moment of NIH and NSF uncertainty is not to give up.27:20
Key Quote
“And so for reasons that are still obscure to me and whoever, I decided to become an immunologist.”
— Leslie Berg5:16
Key Quote
“I've heard this thing about like seed and soil, right?”
— Cindy Leifer12:35
Key Quote
“You have to go, you have to believe the data.”
— Leslie Berg24:17