CD4+ virtual memory: Antigen-inexperienced T cells reside in the naïve, regulatory, and memory T cell compartments at similar frequencies, implications for autoimmunity

Alina I. Marusina, Yoko Ono, Alexander A. Merleev, Michiko Shimoda, Hiromi Ogawa, Elizabeth A. Wang, Kayo Kondo, Laura Olney, Guillaume Luxardi, Yoshinori Miyamura, Tilahun Yilma, Itzel Bustos Villalobos, Jennifer W. Bergstrom, Daniel G. Kronenberg, Athena Soulika, Iannis Adamopoulos, Emanual Michael Maverakis

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)76-88
Number of pages13
JournalJournal of Autoimmunity
StatePublished - Feb 1 2017


  • 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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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