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

Marusina, AI;Ono, Y;Merleev, AA;Shimoda, M;Ogawa, H;Wang, EA;Kondo, K;Olney, L;Luxardi, G;Miyamura, Y;Yilma, TD;Villalobos, IB;Bergstrom, JW;Kronenberg, DG;Soulika, AM;Adamopoulos, IE;Maverakis, E;

It is widely accepted that central and effector memory CD4(+) T cells originate from nave 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 nave 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 nave 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 nave, 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 nave 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.