R01AI187143

Th2 memory in chronic type 2 inflammation - project summary

Immune responses to cancer and chronic infection often collapse, corresponding to progression of disease.

This collapse is not inevitable, however, and both natural and therapeutic exceptions have been shown to occur through re-invigoration of a stem-like progenitor population of T cells.

It remains unknown how aberrant type 2 responses are maintained in the face of chronic antigen exposure, rather than succumbing to immune exhaustion or tolerance.

In a large scale informatic survey of human type 2 inflammation, we recently identified a stinkingly abundant progenitor-like Th2 population in human disease tissue, the Th2 multipotent progenitor (Th2-MPP).

We propose that this aberrant tissue progenitor acts as the mirror image of the exhausted T cells seen in cancer and chronic infection, in this case causing pathology through overactivity of the T cell progenitor system.

This project sets out to define the factors that sustain the Th2 progenitor population using human disease tissue and a novel mouse model.

The experiments in this proposal are designed to reveal the core features of tissue human and mouse Th2 progenitors and to identify the factors that promote their maintenance.

In Aim 1, we will deconstruct the Th2 compartment by comparing aspirin-exacerbated respiratory disease (AERD) and chronic rhinosinusitis with nasal polyposis (CRSwNP), two diseases that are clinically similar, yet thought to be driven by different factors.

Using single-cell RNA-Seq with T cell receptor-Seq, multiomics, spatial in situ transcriptomics, single-cell metabolism assessment, and high-dimensional flow cytometry, we will identify the core and distinct features of the human Th2 compartment including the Th2-MPP population.

In Aim 2, we will utilize a newly-developed chronic, multi-allergen mouse asthma model that recapitulates key features of human tissue type 2 inflammation, including a tissue Th2-MPP population that is sufficient to cause airways hyperactivity on adoptive transfer.

We will utilize this new model to transcriptomically define the mouse Th2 progenitor in fine resolution and test the disease-causing capacity of this population in vivo.

In Aim 3, we will use both a human in vitro system and our new mouse model to test the impact of ongoing T cell receptor signaling, TSLP, IL-33, and glucocorticoid on the Th2 progenitor population.

Through these aims, our proposal will use human and mouse systems and cutting-edge approaches to define in detail a previously unrecognized human Th2 progenitor population present across type 2 disease tissues, with the potential to sustain multiple key Th2 lineages.

These studies will lay the groundwork for targeting this progenitor system, with the goal of disease modification.

Brigham & Womens Hospital

<P>THE GOALS ARE:</P><UL><LI>TO FOSTER FUNDAMENTAL CREATIVE DISCOVERIES, INNOVATIVE RESEARCH STRATEGIES, AND THEIR APPLICATIONS AS A BASIS FOR ULTIMATELY PROTECTING AND IMPROVING HEALTH;</LI><LI>TO DEVELOP, MAINTAIN, AND RENEW SCIENTIFIC HUMAN AND PHYSICAL RESOURCES THAT WILL ENSURE THE NATION'S CAPABILITY TO PREVENT DISEASE;</LI><LI>TO EXPAND THE KNOWLEDGE BASE IN MEDICAL AND ASSOCIATED SCIENCES IN ORDER TO ENHANCE THE NATION'S ECONOMIC WELL-BEING AND ENSURE A CONTINUED HIGH RETURN ON THE PUBLIC INVESTMENT IN RESEARCH; AND</LI><LI>TO EXEMPLIFY AND PROMOTE THE HIGHEST LEVEL OF SCIENTIFIC INTEGRITY, PUBLIC ACCOUNTABILITY, AND SOCIAL RESPONSIBILITY IN THE CONDUCT OF SCIENCE.</LI></UL><P>IN REALIZING THESE GOALS, THE NIH PROVIDES LEADERSHIP AND DIRECTION TO PROGRAMS DESIGNED TO IMPROVE THE HEALTH OF THE NATION BY CONDUCTING AND SUPPORTING RESEARCH:</P><UL><LI>IN THE CAUSES, DIAGNOSIS, PREVENTION, AND CURE OF HUMAN DISEASES;</LI><LI>IN THE PROCESSES OF HUMAN GROWTH AND DEVELOPMENT;</LI><LI>IN THE BIOLOGICAL EFFECTS OF ENVIRONMENTAL CONTAMINANTS;</LI><LI>IN THE UNDERSTANDING OF MENTAL, ADDICTIVE AND PHYSICAL DISORDERS; AND</LI><LI>IN DIRECTING PROGRAMS FOR THE COLLECTION, DISSEMINATION, AND EXCHANGE OF INFORMATION IN MEDICINE AND HEALTH, INCLUDING THE DEVELOPMENT AND SUPPORT OF MEDICAL LIBRARIES AND THE TRAINING OF MEDICAL LIBRARIANS AND OTHER HEALTH INFORMATION SPECIALISTS.</LI></UL>

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Boston, Massachusetts 021156110 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-25-301)