title: CD4+virtual memory: Antigen-inexperienced T cells reside in the naïve, regulatory, and memory T cell compartments at similar frequencies, implications for autoimmunity.
abstract: It is widely accepted that central and effector memory CD4+T cells originate from naïve T cells after they have encountered their cognate antigen in the setting of appropriate co-stimulation. However, if this were true the diversity of T cell receptor (TCR) sequences within the naïve T cell compartment should be far greater than that of the memory T cell compartment, which is not supported by TCR sequencing data. Here we demonstrate that aged mice with far fewer naïve T cells, respond to the model antigen, hen eggwhite lysozyme (HEL), by utilizing the same TCR sequence as their younger counterparts. CD4+T cell repertoire analysis of highly purified T cell populations from naive animals revealed that the HEL-specific clones displayed effector and central "memory" cell surface phenotypes even prior to having encountered their cognate antigen. Furthermore, HEL-inexperienced CD4+T cells were found to reside within the naïve, regulatory, central memory, and effector memory T cell populations at similar frequencies and the majority of the CD4+T cells within the regulatory and memory populations were unexpanded. These findings support a new paradigm for CD4+T cell maturation in which a specific clone can undergo a differentiation process to exhibit a "memory" or regulatory phenotype without having undergone a clonal expansion event. It also demonstrates that a foreign-specific T cell is just as likely to reside within the regulatory T cell compartment as it would the naïve compartment, arguing against the specificity of the regulatory T cell compartment being skewed towards self-reactive T cell clones. Finally, we demonstrate that the same set of foreign and autoreactive CD4+T cell clones are repetitively generated throughout adulthood. The latter observation argues against T cell-depleting strategies or autologous stem cell transplantation as therapies for autoimmunity-as the immune system has the ability to regenerate pathogenic clones.
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Sacramento, Davis, CA 95817, United States.
authors.forename: Alina I
authors.initials: AI
authors.lastname: Marusina
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Sacramento, Davis, CA 95817, United States.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ono
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Sacramento, Davis, CA 95817, United States.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Merleev
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Sacramento, Davis, CA 95817, United States.
authors.forename: Michiko
authors.initials: M
authors.lastname: Shimoda
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Sacramento, Davis, CA 95817, United States.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Sacramento, Davis, CA 95817, United States.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Wang
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Sacramento, Davis, CA 95817, United States.
authors.forename: Kayo
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Sacramento, Davis, CA 95817, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Olney
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Sacramento, Davis, CA 95817, United States.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Luxardi
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Sacramento, Davis, CA 95817, United States.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Miyamura
authors.affiliation: International Laboratory of Molecular Biology for Tropical Disease Agents, School of Veterinary Medicine, University of California, Davis, CA 95616, United States; Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA 95616, United States.
authors.forename: Tilahun D
authors.initials: TD
authors.lastname: Yilma
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Sacramento, Davis, CA 95817, United States.
authors.forename: Itzel Bustos
authors.initials: IB
authors.lastname: Villalobos
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Sacramento, Davis, CA 95817, United States.
authors.forename: Jennifer W
authors.initials: JW
authors.lastname: Bergstrom
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Sacramento, Davis, CA 95817, United States.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Kronenberg
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Sacramento, Davis, CA 95817, United States.
authors.forename: Athena M
authors.initials: AM
authors.lastname: Soulika
authors.affiliation: Department of Internal Medicine, School of Medicine, University of California, Sacramento, Davis, CA 95817, United States.
authors.forename: Iannis E
authors.initials: IE
authors.lastname: Adamopoulos
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Sacramento, Davis, CA 95817, United States. Electronic address: emaverakis@ucdavis.com.
authors.forename: Emanual
authors.initials: E
authors.lastname: Maverakis
mesh_terms: D000367:Age Factors; D000818:Animals; D000941:Antigens / Q000276:immunology; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002645:Chickens; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004527:Egg Proteins / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D007156:Immunologic Memory; D016130:Immunophenotyping; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D051379:Mice; D010641:Phenotype; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D000941:Antigens; D004527:Egg Proteins
keywords: Autoimmunity; CD4 T cell; Driver T cells; Experimental autoimmune encephalomyelitis; Hematopoietic stem cell transplantation; Memory T cells; Next generation sequencing; T cell repertoire analysis; T regulatory cells; Virtual memory