# PATHWAYS OF T LYMPHOCYTE ACTIVATION

> **NIH NIH R01** · STANFORD UNIVERSITY · 1992 · $124,132

## Abstract

T lymphocytes capable of responding to virtually any antigen on invading
pathogens or transplanted tissue are produced in the thymus as a result
of selection and intrathymic differentiation.  These cells migrate to
the peripheral lymphoid organs and upon encountering foreign antigen
undergo an orderly sequence of events that results in proliferation and
acquisition of immunologic function.  During this process they
coordinate the activity of other cells involved in the immune response
by controlling cell fate decisions and proliferation of B cells,
macrophages and granulocytes through the production of cytokines and
cell-cell interactions.  We propose to explore the pathways used by the
T cell antigen receptor to communicate with genes necessary for
immunologic activation.  Most of our attention will be directed toward
the least understood part of the pathway which connects Ca2+-dependent
events and tyrosine kinase substrates to the activation of certain
genes, such as IL-2 that are critical for proliferation.  A
comprehensive and unbiased genetic approach has been devised to produce
mutations in the proteins carrying signals from the antigen receptor to
the IL-2 gene.  Cells having these mutations will be placed into
complementation groups by analysis of heterokaryons formed between the
different clones.  Each complementation group will be characterized to
localize the site of action of the defective protein.  Genes able to
complement the mutant phenotype will be cloned by transfecting cDNA
expression libraries into the mutants and rescuing plasmids able to
restore signal transmission.  This genetic approach will be enhanced by
an analysis of the nuclear events essential for IL-2 gene activation
using an in vitro transcription system developed in our laboratory that
faithfully reflects the complex requirements for the activation of the
IL-2 gene.  We will use this system to identify proteins (kinases,
proteases, etc) necessary for the activation of two transcription
factors, OAP (Oct-1 Associated Protein) and NF-AT (Nuclear Factor of
Activated T cells), which are required for IL-2 gene activation and
specifically activated by triggering the antigen receptor.  By
continuing this process of working backward from proteins essential IL-2
gene activation we expect, by the end of the 5 year granting period, to
define the processes used by the antigen receptor to communicate with
genes in the nucleus.

## Key facts

- **NIH application ID:** 3178801
- **Project number:** 5R01CA039612-08
- **Recipient organization:** STANFORD UNIVERSITY
- **SAM.gov UEI:** HJD6G4D6TJY5
- **Principal Investigator:** Gerald R. Crabtree
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $124,132
- **Award type:** 5
- **Project period:** 1985-05-01 → 1996-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3178801

## Citation

> US National Institutes of Health, RePORTER application 3178801, PATHWAYS OF T LYMPHOCYTE ACTIVATION (5R01CA039612-08). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/3178801. Licensed CC0.

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