Similar but different: virtual memory CD8 T cells as a memory-like cell population

Immunological memory is a phenomenon where the immune system can respond more rapidly to pathogens and immunological challenges that it has previously encountered. It is defined by several key hallmarks. After an initial encounter, immune cells (1) expand and (2) differentiate to form memory cell populations. Memory cells are (3) long-lived and (4) facilitate more rapid immune responses to subsequent infection because of (i) an increase in cell number, (ii) a decrease in the signaling threshold required for entry into cell cycle or effector function and (iii) localization of cells to tissue sites for surveillance. Classically, immunological memory has been antigen specific but it is becoming apparent that mechanisms of immunological memory can be co-opted by innate or antigen-inexperienced immune cells to generate heterogeneity in immune responses. One such cell is the virtual memory CD8 T (T_VM ) cell, which is a semi-differentiated but antigen-naïve CD8 T-cell population. This review will summarize current knowledge of how T_VM cells are generated, their memory-like hallmarks, how they are maintained during steady state, infection and aging, and propose a model to integrate key signaling pathways during their generation.