TY - JOUR
T1 - CD4+ virtual memory
T2 - Antigen-inexperienced T cells reside in the naïve, regulatory, and memory T cell compartments at similar frequencies, implications for autoimmunity
AU - Marusina, Alina I.
AU - Ono, Yoko
AU - Merleev, Alexander A.
AU - Shimoda, Michiko
AU - Ogawa, Hiromi
AU - Wang, Elizabeth A.
AU - Kondo, Kayo
AU - Olney, Laura
AU - Luxardi, Guillaume
AU - Miyamura, Yoshinori
AU - Yilma, Tilahun
AU - Villalobos, Itzel Bustos
AU - Bergstrom, Jennifer W.
AU - Kronenberg, Daniel G.
AU - Soulika, Athena
AU - Adamopoulos, Iannis
AU - Maverakis, Emanual Michael
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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.
AB - 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.
KW - Autoimmunity
KW - CD4 T cell
KW - Driver T cells
KW - Experimental autoimmune encephalomyelitis
KW - Hematopoietic stem cell transplantation
KW - Memory T cells
KW - Next generation sequencing
KW - T cell repertoire analysis
KW - T regulatory cells
KW - Virtual memory
UR - http://www.scopus.com/inward/record.url?scp=85007039349&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85007039349&partnerID=8YFLogxK
U2 - 10.1016/j.jaut.2016.11.001
DO - 10.1016/j.jaut.2016.11.001
M3 - Article
C2 - 27894837
AN - SCOPUS:85007039349
VL - 77
SP - 76
EP - 88
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
SN - 0896-8411
ER -