# Mechanisms and consequences of antigen-dependent T cell homing for adoptive immunotherapies

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $418,750

## Abstract

Project Summary/Abstract
Adoptive cell therapy (ACT) with activated and expanded T or CAR T cells may be used to treat infections or
tumors and ACT with T or CAR T regulatory cells are in clinical trials to control autoimmunity and allograft
rejection. Many but not all patients benefit. The success of ACT depends upon T cell homing to relevant tissue
sites. Normal circulating T effector memory or T regulatory cells can enter a tissue in response to their cognate
antigen being displayed on the surface of the local microvascular ECs in a process triggered by TCR and
modulated by costimulation. We hypothesize that antigen presentation by human endothelial cells (ECs)
will recruit adoptively transferred in vitro expanded T or CAR T effector and regulatory cells to specific
peripheral tissue sites in a process modulated by specific EC co-stimulators. In specific aim 1, we will
test this hypothesis in vitro in models we have developed using endothelial cell monolayers in flow chambers
to model in vivo conditions. We will expand our in vitro assys to include an examination of the effects that TCR-
induced transendothelial migration (TEM) has on the T cells at the single cell level. In the case of CAR T cells,
we will determine the most important costimulator receptor molecule motifs to be incorporated into the CAR for
optimal TEM. We will also determine if human ECs have the capacity to cross-present or be “cross-dressed” by
antigens allowing EC presentation of antigen to influence cancer immunotherapy. Finally, we will use a model
we developed for studying adoptively transferred human T cell responses to synthestic microvessels
assembled from human ECs, allowing genetic manipulation of the signals human ECs can provide. In aim 2
we will conduct similar experiments using T and CAR T regulatory cells. Successful completion of these aims
will provide important information for extending the range of patients who may benefit from ACT.

## Key facts

- **NIH application ID:** 10654215
- **Project number:** 1R01AI166364-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Thomas David Manes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $418,750
- **Award type:** 1
- **Project period:** 2023-08-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10654215

## Citation

> US National Institutes of Health, RePORTER application 10654215, Mechanisms and consequences of antigen-dependent T cell homing for adoptive immunotherapies (1R01AI166364-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10654215. Licensed CC0.

---

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