Cellular and molecular regulation of tissue-resident memory CD8+ T cell proliferation

The National Institute of Allergy and Infectious Diseases awarded Versiti Blood Health, Inc. $510,000 on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to support research on cellular and molecular regulation of tissue-resident memory CD8+ T cell proliferation.

The project investigates how tissue-resident memory CD8+ T cells maintain their capacity for lifelong cell cycling and self-renewal independent of circulating immune populations. The research characterizes the cellular and molecular dynamics of T cell division to identify regulatory mechanisms as potential therapeutic targets. The applicant's hypothesis posits that tissue-resident memory CD8+ T cells proliferate via a hybrid state, enabling individual cells to exhibit both stem cell-like proliferation and advanced differentiation for effector functions. The DP2 mechanism funding accelerates innovative research unlikely to receive support through traditional mechanisms and supports the applicant's newly independent research group, which began in August 2025.

Work is performed in Wauwatosa, Wisconsin, with a period of performance extending from September 1, 2026, through August 31, 2031. The award is structured as a Project Grant, the standard assistance type under this NIH program.

Abstract

Tissue-resident immune cells are seeded within tissues starting during development and continuing throughout life. During this process, differentiation occurs into functionally distinct and tissue-adapted subsets which can then persist for years, decades, or even life. However, our understanding of immunology is largely skewed towards easily accessible circulating populations and in vitro cultures. This proposal addresses tissue-resident memory CD8+ T cells (TRM), which are typically elicited by infection and serve as first responders. TRM allow the immune system to quickly recreate a prior immune response if the eliciting pathogen later returns and to do so at the site of RE-exposure before dissemination occurs. TRM are capable of locally controlling infection as well as cancer. Another remarkable feature of TRM is their seemingly lifelong capacity to undergo cell cycling. This is essential for the very existence of stable TRM populations independent of the circulation. How this process occurs is unclear, and IT is controversial whether such proliferation is restricted to stem cell-like subsets. The applicant proposes to address this knowledge GAP by characterizing the cellular and molecular dynamics of cell division for TRM to identify novel regulatory mechanisms as potential therapeutic targets. The hypothesis underlying this application is that TRM proliferate via a hybrid state, meaning that an individual cell can exhibit both stem cell-like proliferation and advanced differentiation to enable effector functions. Funding via the DP2 mechanism would accelerate this innovative and interdisciplinary research unlikely to be supported via traditional funding mechanisms and kickstart the applicant's independent group (began august 2025). Identifying the cellular and molecular drivers of TRM self-renewal is likely to provide novel targets for therapeutic enhancement and ablation of tissue-resident immunity, with potential applications in infectious disease, autoimmunity, and cancer.