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Theses Doctoral

Tissue-wide dynamics of human anti-viral immunity

Poon, Maya

The human body is exposed to a multitude of prevalent viruses, requiring ongoing surveillance and protection by the immune system. Maintenance of human anti-viral adaptive immunity in diverse tissue sites is determined by a multitude of factors and critical for long-term protection against repeat exposure to viral infection. Yet, studies of anti-viral immunity have primarily been limited to animal studies and studies of peripheral blood in humans. Studies in mice have demonstrated that memory T cells in tissues provide superior protection against viral infection compared to circulating T cells, particularly tissue-resident memory T cells (TRM), which remain in tissues long-term without re-entering circulation. However, much remains to be understood about how anti-viral immune responses are maintained in human tissues and how adaptive immune cells in various tissues sites function upon re-exposure to viral antigens. We have established a human tissue resource through a collaboration with LiveOnNY, a local organ procurement organization, to obtain blood and multiple lymphoid and mucosal sites from donors of all ages. Using this tissue resource, we employed comprehensive cellular and molecular analysis to investigate tissue immunity to three prevalent but distinct viruses—influenza A, CMV, and SARS-CoV-2.

We compared CD8+ T cells recognizing ubiquitous and longstanding viruses influenza A and CMV across multiple tissue sites of 58 organ donors ages 1-78 years in order to elucidate how covariates of virus, tissue, age, and sex impact the anti-viral immune response. Using flow cytometry, T cell receptor repertoire sequencing, functional assays, and single-cell transcriptional profiling, we showed that virus specificity and tissue localization are the primary drivers of anti-viral T cell immune responses in the human body, with age and sex further influencing T cell subset differentiation. Specifically, virus specificity correlated with virus-specific T cell distribution, memory subset differentiation, and clonal repertoire, while tissue localization determined overall subset distribution and functional responses. We further investigated the tissue-localized immune response to emergent SARS-CoV-2.

By examining multiple tissues of organ donors who had recovered from natural infection by SARS-CoV-2, we showed that adaptive memory immune responses persisted months after infection, with memory T and B cells preferentially localized in the lung and lung-associated lymph node. Persisting memory cell populations included tissue-resident T and B cells, particularly in the lung, as well as germinal center B cells in the lung-associated lymph node along with follicular helper T cells, indicating ongoing generation of humoral immunity. Together, these findings highlight the importance of tissue-localized anti-viral immunity and help to define characteristics of site-specific protective immunity that may be leveraged for the development of more effective treatment and prevention strategies.

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More About This Work

Academic Units
Cellular, Molecular and Biomedical Studies
Thesis Advisors
Farber, Donna L.
Degree
Ph.D., Columbia University
Published Here
December 22, 2021