Going Virtual as a Memory-Phenotype T Lymphocyte

Conventional or 'true' memory CD8⁺ T cells (T_TM) arise from immunologically naive T cells that circulate in the periphery after selection in the thymus. During infection or immunization by a foreign antigen, naive T cells can receive antigen-specific activation signals after recognition of MHC-antigenic peptide complexes. But the CD8⁺ T-cell population in immunologically naive hosts is not restricted to circulating naive T cells expecting cognate antigen encounter. Indeed, memory-phenotype T cells (T_MP) develop in the absence of foreign antigen encounter and therefore exist in naive, pathogen-free, as well as germ-free conditions. T_MP have been shown to mediate bystander cell killing through innate mechanisms, as well as rapidly respond to cognate antigen stimulation. While the existence of foreign antigen-inexperienced T_MP is now well acknowledged in laboratory mice, and also recognized in humans, the extensive nomenclature used for their description challenges the overall understanding of their multiple functions in health and disease. This article discusses the current understanding and controversies on the origin, maintenance and functions of the various populations recognized as T_MP and highlights some potential challenges for deciphering their fate.