Functional Consequences of Memory Inflation after Solid Organ Transplantation

CMV is a major infectious complication following solid organ transplantation. Reactivation of CMV leads to memory inflation, a process in which CD8 T cells expand over time. Memory inflation is associated with specific changes in T cell function, including increased oligoclonality, decreased cytokin...

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Published inThe Journal of immunology (1950) Vol. 207; no. 8; pp. 2086 - 2095
Main Authors Higdon, Lauren E, Schaffert, Steven, Cohen, Rachel H, Montez-Rath, Maria E, Lucia, Marc, Saligrama, Naresha, Margulies, Kenneth B, Martinez, Olivia M, Tan, Jane C, Davis, Mark M, Khatri, Purvesh, Maltzman, Jonathan S
Format Journal Article
LanguageEnglish
Published England 15.10.2021
Subjects
Adult
Aged
Antigens, Viral - immunology
CD8-Positive T-Lymphocytes - immunology
Cell Differentiation
Cell Proliferation
Clone Cells
Cytomegalovirus - physiology
Cytomegalovirus Infections - immunology
Female
Heart Transplantation
Humans
Immunologic Memory
Kidney Transplantation
Lymphocyte Activation
Male
Middle Aged
Postoperative Complications
Receptors, Antigen, T-Cell, alpha-beta - genetics
Single-Cell Analysis
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Summary:CMV is a major infectious complication following solid organ transplantation. Reactivation of CMV leads to memory inflation, a process in which CD8 T cells expand over time. Memory inflation is associated with specific changes in T cell function, including increased oligoclonality, decreased cytokine production, and terminal differentiation. To address whether memory inflation during the first year after transplantation in human subjects alters T cell differentiation and function, we employed single-cell–matched TCRαβ and targeted gene expression sequencing. Expanded T cell clones exhibited a terminally differentiated, immunosenescent, and polyfunctional phenotype whereas rare clones were less differentiated. Clonal expansion occurring between pre- and 3 mo posttransplant was accompanied by enhancement of polyfunctionality. In contrast, polyfunctionality and differentiation state were largely maintained between 3 and 12 mo posttransplant. Highly expanded clones had a higher degree of polyfunctionality than rare clones. Thus, CMV-responsive CD8 T cells differentiated during the pre- to posttransplant period then maintained their differentiation state and functional capacity despite posttransplant clonal expansion.
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These authors contributed equally to this work.
Current affiliation: Washington University in St. Louis, Department of Neurology and The Andrew M. and Jane. M Bursky Center for Human Immunology & Immunotherapy Programs, St. Louis, MO 63110.
Current affiliation: Notable Labs, Inc., Foster City, CA 94404
Current affiliation: Quell Therapeutics Limited, London, United Kingdom
Author contributions: LEH completed experiments. LEH, SS, RHC, MMR, NS completed analyses of the data. LEH, ML, NS, OMM, MMD, and JSM contributed to experimental design. LEH, SS, PK, and JSM wrote the majority of the manuscript. The order of co-first authors was selected as LEH had greater involvement in initial study design and SS contributed equally to all subsequent steps. MMR was the consulting statistician. KBM and JSM collected the patient specimens. KBM, JCT provided clinical insight in the writing of the manuscript. OMM, MMD advised in the writing of the manuscript.
ISSN:0022-1767
1550-6606
1550-6606
DOI:10.4049/jimmunol.2100405