# Human T cell-mediated immunity to viruses in tissues and circulation

> **NIH NIH U19** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $292,943

## Abstract

PROJECT 1: PROJECT SUMMARY
Understanding anti-viral immunity in humans requires investigating the complexity of the human immune
response—sampling diverse groups of individuals, and studying immune responses where they function and
are maintained in tissue sites throughout the body. T cells coordinate anti-viral adaptive immunity through their
activation and differentiation in lymphoid tissues, subsequent migration to tissue sites of infection, and their
long-term maintenance as virus-specific memory T cell subsets in circulation and in diverse tissue sites. The
majority of memory T cells throughout the body are non-circulating, tissue-resident memory T (TRM) cells
which can mediate protective immunity, as demonstrated in mouse models, and are therefore important for
understanding and targeting anti-viral immunity. Studying TRM is challenging in humans where blood remains
the most readily sampled and studied site. Over 10 years ago, my laboratory set up a human tissue resource
to obtain multiple lymphoid and mucosal tissues from individual organ donors, and have optimized the study of
immune cells from over 500 donors, revealing precise tissue-regulated compartmentalization and site-specific
adaptations. In our studies under the current HIPC award, we identified how T cells-specific for ubiquitous
viruses are distributed and function in tissues, with an initial focus on cytomegalovirus (CMV)--later extended to
influenza-specific and more recently to SARS-CoV-2-specific immunity. Our results reveal virus-specific
adaptive immune responses are controlled on multiple levels—by the virus itself, including its pathogenesis
and tissue targets, the tissue site which influences T cell functionality, age which correlates with T cell
differentiation and dissemination, and sex-specific variations. Our central hypothesis is that the virus, tissue,
age and sex direct specific and measurable influences on the anti-viral T cell response that together influence
its functionality and protective efficacy. In the proposed study, we will apply systems-wide approaches to
analyze the complexity and heterogeneity of the human T cell response through a comprehensive assessment
of their profiles across blood and tissues. In Aim 1 we will quantify the contribution of virus type, tissue, age,
and sex in anti-viral T cell phenotypes, and understanding how these factors interact in predictive models for
human T cell immunity. In aim 2, we will analyze virus-specific T cell functional states and clonal signatures
across diverse tissue sites to address how virus-specific T cells integrate both site- and virus-specific features
into their clonal and functional signatures. We will use combinatorial single cell profiling by CITE-Seq with
determination of paired T cell receptor clone sequences of CMV-, influenza-, and SARS-CoV-2-responding
CD4+ and CD8+T cells following stimulation with viral epitope pools. Functional and tissue-specific signatures
will be validated by cytokine an...

## Key facts

- **NIH application ID:** 10419870
- **Project number:** 2U19AI128949-06
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Donna L. Farber
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $292,943
- **Award type:** 2
- **Project period:** 2017-01-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10419870

## Citation

> US National Institutes of Health, RePORTER application 10419870, Human T cell-mediated immunity to viruses in tissues and circulation (2U19AI128949-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10419870. Licensed CC0.

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