# Harnessing NKT Cell Activation by Glycolipids

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT STORRS · 2021 · $518,569

## Abstract

Natural killer T (NKT) cells are potent, innate-like T cells involved in the regulation of immune responses
ranging from reaction to pathogens and tumors to the development or suppression of autoimmunity. Activation
of NKT cells may provide new therapies for viral and bacterial infections, for cancer and for a range of
autoimmune conditions, such as Type I diabetes, multiple sclerosis and lupus. NKT cells are divided into two
major classes, Type I (iNKT) and Type II NKT cells. Both are activated by glycolipids which serve as ligands for
an antigen presenting protein, CD1d. Glycolipid activation of iNKT cells has been extensively studied for more
than two decades. Much less is known about the Type II cells. Crucial to utilizing NKT cell stimulation
therapeutically is the ability to control the nature of the response. Although a number of glycolipids that elicit
Th1 (relevant for treatment of cancer and infections) or Th2 (relevant for autoimmune conditions) cytokines
from iNKT cells have been identified, the bias often disappears in vivo, or the compounds fail to activate
human iNKT cells. Another need in the NKT cell arena is identification of potent activators of sulfatide-reactive
Type II NKT cells and development of baseline structural activity relationships in these much less explored, but
more abundant in humans, NKT cells. In collaboration with immunologists, structural biologists and physical
chemists this proposal has two major thrusts: 1) Design, synthesize and evaluate carbohydrate modified
glycolipids that elicit a Th1 biased cytokine response from iNKT cells in contexts relevant for the development
of human anti-cancer therapies. To realize this goal three hypotheses will be tested: a) More potent, clinically
relevant C4”-analogs can be identified; b) Dual modifications of the ceramide and C6”-position of the sugar can
be used to enhance potency and Th1 bias; c) Photochemically cross-linked glycolipid/CD1d conjugates can be
used as an avenue for antigen delivery and to further enhance Th1 bias. Each hypothesis is based on solid
preliminary studies involving human cell lines and or a humanized mouse model. The studies will elucidate the
potential of the carbohydrate moiety for enhancing Th1 bias. The second major thrust is: 2) To continue to
build understanding of sulfatide-reactive Type II NKT cells. Most evidence has suggested that the activation of
these Type II cells counter-regulates iNKT cells; however results from the current funding period have shown
that certain sulfatides elicit responses similar to iNKT cells. Current results and outcomes from new, proposed
sulfatides are being/will be used to develop and refine pharmacophoric models for designing potent agonists
for Type II NKT cells.

## Key facts

- **NIH application ID:** 10250477
- **Project number:** 5R01GM111849-07
- **Recipient organization:** UNIVERSITY OF CONNECTICUT STORRS
- **Principal Investigator:** Amy Howell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $518,569
- **Award type:** 5
- **Project period:** 2014-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10250477

## Citation

> US National Institutes of Health, RePORTER application 10250477, Harnessing NKT Cell Activation by Glycolipids (5R01GM111849-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10250477. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*