# ONTOGENIC DEVELOPMENT OF LYMPHOCYTES

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 1993 · $229,463

## Abstract

Retinol is an essential cofactor in growth regulation of lymphocytes and
other cells.  Intracellularly, retinol is converted into 14 hydroxy-retro-
retinol (14HRR), the first naturally occurring retro-retinoid to be
discovered.  14HRR substitutes for retinol at 100-fold lower concentration
and therefore qualifies as a second messenger molecule.

The biosynthesis of 14HRR in lymphocytes involves as an intermediate 13,14
dihydroxy retinol (DHR), also a new retinol discovered by us.  This
conclusion is based on kinetic analyses indicating that DHR synthesis
precedes that of 14HRR, and furthermore on biochemical evidence
establishing a direct precursor-product relationship.  The rate of retinol
consumption is dependent on the state of activation, being low in resting
T cells but accelerating approxiately 10-fold during activation of T cells.
The increase in retinol consumption is transient and is parallel by
synthesis of DHR and 14HRR.  These data strongly imply regulation of
retinoid metabolism and form another argument for the view that 14HRR is a
second messenger molecule.

Studies on activation requirements in T cells have shown that retinol or
14HRR needs to be present during the first day of activation.  When blast
transformation has occurred and T cells proliferate, they become
independent of retinol or 14HRR.  The early dependence on retinol cannot be
overcome by lymphokines (IL-1, 1-2, IL-4, IL-6 or TNFalpha) but in the
presence of IFN-gamma substantial T cell activation can also occur in the
absence of retinoids.

While 14-HRR-responsive genes have not been identified, we have noted small
but reproducible influences on the activation of immediate early genes.
Whereas it is unlikely that the dramatic difference in cellular responses
elicited by retinol can be explained on the basis of immediate early gene
regulation, the observed transcriptional enhancement implies a nuclear site
of action.  A search for the putative nuclear receptor is in progress.

## Key facts

- **NIH application ID:** 3176448
- **Project number:** 5R01CA038351-16
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **SAM.gov UEI:** KUKXRCZ6NZC2
- **Principal Investigator:** ULRICH G HAMMERLING
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $229,463
- **Award type:** 5
- **Project period:** 1984-04-01 → 1996-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3176448

## Citation

> US National Institutes of Health, RePORTER application 3176448, ONTOGENIC DEVELOPMENT OF LYMPHOCYTES (5R01CA038351-16). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3176448. Licensed CC0.

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