Tissue reservoirs of antiviral T cell immunity in persistent human CMV infection

Gordon, Claire L.; Miron, Michelle; Thome, Joseph J.C.; Matsuoka, Naoki; Weiner, Joshua; Rak, Michael; Igarashi, Suzu; Granot, Tomer; Lerner, Harvey; Goodrum, Felicia; Farber, Donna L.

doi:10.1084/jem.20160758

“…We have established a human tissue resource to obtain blood, multiple lymphoid and mucosal tissues from previously healthy organ donors, enabling analysis of T cell compartmentalization and maintenance throughout life (Gordon et al, 2017; Sathaliyawala et al, 2013; Thome et al, 2016a; Thome et al, 2016b; Thome et al, 2014). We present here transcriptional, phenotypic, and functional analyses which define human TRM as a distinct subset in multiple sites.…”

Section: Introductionmentioning

confidence: 99%

Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites

Kumar

¹

,

Wei-hua

²

,

Miron

³

et al. 2017

Self Cite

View full text Add to dashboard Cite

SUMMARY Tissue-resident memory T cells (TRM) in mice mediate optimal protective immunity to infection and vaccination, while in humans, the existence and properties of TRM remain unclear. Here, we use a unique human tissue resource to determine whether human tissue memory T cells comprise a distinct subset in diverse mucosal and lymphoid tissues. We identify a core transcriptional profile within the CD69+ subset of memory CD4+ and CD8+ T cells in lung and spleen that is distinct from that of CD69−TEM cells in tissues and circulation, and defines human TRM based on homology to the transcriptional profile of mouse CD8+TRM. Human TRM in diverse sites exhibit increased expression of adhesion and inhibitory molecules, produce both pro-inflammatory and regulatory cytokines, and have reduced proliferation compared with circulating TEM, suggesting unique adaptations for in situ immunity. Together our results provide a unifying signature for human TRM and a blueprint for designing tissue-targeted immunotherapies.

show abstract

“…We have established a human tissue resource to obtain blood, multiple lymphoid and mucosal tissues from previously healthy organ donors, enabling analysis of T cell compartmentalization and maintenance throughout life (Gordon et al, 2017;Sathaliyawala et al, 2013;Thome et al, 2016a;Thome et al, 2016b;Thome et al, 2014). We present here transcriptional, phenotypic, and functional analyses which define human TRM as a distinct subset in multiple sites.…”

Section: Introductionmentioning

confidence: 99%

Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites

Kumar

¹

,

Wei-hua

²

,

Miron

³

et al. 2018

Self Cite

View full text Add to dashboard Cite

SUMMARYTissue-resident memory T cells (TRM) in mice mediate optimal protective immunity to infection and vaccination, while in humans, the existence and properties of TRM remain unclear. Here, we use a unique human tissue resource to determine whether human tissue memory T cells comprise a distinct subset in diverse mucosal and lymphoid tissues. We identify a core transcriptional profile within the CD69 + subset of memory CD4 + and CD8 + T cells in lung and spleen that is distinct from that of CD69 − TEM cells in tissues and circulation, and defines human TRM based on homology to the transcriptional profile of mouse CD8 + TRM. Human TRM in diverse sites exhibit increased expression of adhesion and inhibitory molecules, produce both pro-inflammatory and regulatory cytokines, and have reduced proliferation compared with circulating TEM, suggesting * Correspondence and lead contact: df2396@cumc.columbia.edu. 6 These authors contributed equally. 7 Senior author Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AUTHOR CONTRIBUTIONS ACCESSION NUMBERSThe accession number for the RNA-Seq data reported in this paper is GEO: GSE94964. HHS Public Access eTOC BlurbKumar et al. identify a core transcriptional and phenotypic signature which defines human TRM for both CD4 + and CD8 + T cells that is preserved across diverse individuals and in mucosal and lymphoid sites.

show abstract

“…We, along with our collaborators, have embarked on a multi-dimensional analysis of innate and adaptive immune cells in diverse tissue types (blood-rich, mucosal, lymphoid) from research-consented organ donors through a protocol and collaboration with our local organ procurement organization in the New York Metropolitan area, LiveOnNY (17–24). Using this resource, we have analyzed immune cell subset distribution and heterogeneity throughout the body and across the lifespan in tissues from over 100 individuals (19, 21, 23), revealing that T cell and dendritic cell subset composition and differentiation are specific to the tissue site, with some age-associated changes in specific compartments (17, 21, 23, 24).…”

Section: Introductionmentioning

confidence: 99%

Human immunology studies using organ donors: Impact of clinical variations on immune parameters in tissues and circulation

Carpenter

¹

,

Granot

²

,

Matsuoka

³

et al. 2018

American Journal of Transplantation

View full text Add to dashboard Cite

Organ donors are sources of physiologically healthy organs and tissues for life-saving transplantation, and have been recently used for human immunology studies which are typically confined to the sampling of peripheral blood. Donors comprise a diverse population with different causes of death and clinical outcomes during hospitalization, and the effects of such variations on immune parameters in blood and tissues are not known. We present here a coordinate analysis of innate and adaptive immune components in blood, lymphoid (bone marrow, spleen, lymph nodes), and mucosal (lungs, intestines) sites from a population of brain-dead organ donors (2 months-93 years; n = 291) across eight clinical parameters. Overall, the blood of donors exhibited similar monocyte and lymphocyte content and low serum levels of pro-inflammatory cytokines as healthy controls; however, donor blood had increased neutrophils and serum levels of IL-8, IL-6, and MCP-1 which varied with cause of death. In tissues, the frequency and composition of monocytes, neutrophils, B lymphocytes and T cell subsets in lymphoid or mucosal sites did not vary with clinical state, and was similar in donors independent of the extent of clinical complications. Our results reveal that organ donors maintain tissue homeostasis, and are a valuable resource for fundamental studies in human immunology.

show abstract

Tissue reservoirs of antiviral T cell immunity in persistent human CMV infection

Abstract: Using a novel human organ donor tissue resource, Gordon et al. reveal how CMV-specific T cells are distributed and function in multiple sites in the context of viral persistence, revealing new insights into immune control of CMV in the body.

Cited by 128 publications

References 59 publications

Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites

Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites

Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites

Human immunology studies using organ donors: Impact of clinical variations on immune parameters in tissues and circulation

Contact Info

Product

Resources

About