# Project 2:  Genes required for dendritic cell responses to pathogens and T cells

> **NIH NIH U19** · HARVARD MEDICAL SCHOOL · 2021 · $690,783

## Abstract

The dendritic cells (DCs) of the mammalian innate immune system are responsible for detection of microbial
encounters and the initiation of inflammation and adaptive immunity. This central role of DCs in host physiology
has attracted much attention, and these cells are the subject of active investigation. Despite the appreciation of
the importance of DCs, there remain large and fundamental gaps in our knowledge of their mechanisms of
regulation. For instance, DCs encode several receptors that detect bacterial lipopolysaccharides (LPS), yet the
functions of only one (TLR4) have been examined extensively. Recent work by us and others have identified
the LPS receptors CD14 and caspase-11 as being capable of inducing novel signaling pathways that proceed
either upstream of TLR4 (CD14) or in parallel to TLR4 (caspase-11). The collective actions of CD14, TLR4 and
caspase-11 are important for DC activation and host defense, yet their mechanisms of action are poorly
defined. Thus, significant gaps in our knowledge exist to explain the earliest stages of DC interactions with
bacteria. We also lack an understanding of how DCs interact with T cells at later stages of infection, yet it is
clear that these interactions lead to profound changes in the activities of both cell types. Much of the research
into these interactions has focused on how DCs promote changes in T cell activities. In contrast, we have a
minimal understanding of how T cells influence the activity of DCs. In this application, we propose to fill these
gaps in our knowledge of DC biology through forward genetic screening for novel regulatory factors in mice.
This approach is facilitated by recent advances in genome editing provided by CRISPR-based technologies. A
pipeline of gene discovery will be generated through the use of established and emerging FACS-based
assays. These assays will be used in vivo and ex vivo to identify DCs that are deficient for regulators of DC
interactions with microbes or T cells. All screens will depend on significant interactions between the
informatics, mouse perturbation and CRISPR library Cores associated with this U19 application. Subsequent
functional analysis of candidate regulatory proteins will be performed in collaboration with other investigators
on this grant. The cumulative result of these efforts will be a series of novel gene sets that should define
pathways and processes that explain numerous aspects of DC biology as they relate to host defense.

## Key facts

- **NIH application ID:** 10207350
- **Project number:** 5U19AI133524-05
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Nir Hacohen
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $690,783
- **Award type:** 5
- **Project period:** 2017-07-05 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10207350

## Citation

> US National Institutes of Health, RePORTER application 10207350, Project 2:  Genes required for dendritic cell responses to pathogens and T cells (5U19AI133524-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10207350. Licensed CC0.

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