Fig 8. Proposed model of T cell activation and memory T cell differentiation.

Upon activation of naïve T cells, Teff^Early (CD127^- CD62L^hi CD27⁺) are generated, which contain precursors to both effector and memory T cells. Depending on the presence of antigen (or leukopenia) in their environment, they can progress toward maturation of effector T cells, Teff^Int, Teff^Late subsets, or in an uninfected environment, towards differentiation into Tcm and then Tem subsets, the latter being promoted by low-level chronicity. Upon downregulation of CD62L, Teff lose survival potential and become terminal Teff; however, surviving mature Teff can become CD127^hi, and expand when re-activated and promote protection. Tmem can proliferate without downregulating CD127 in conditions of low antigen exposure (Fig 4B). Dotted arrows show less common events, or those dependent on environmental changes. Tmem can become Teff again in conditions of re-exposure to higher antigen loads (S2B Fig). We have also observed the more terminally differentiated subsets re-expressing CD62L, suggesting plasticity in this process. The degree of differentiation to central or effector memory T cells from Teff^Early is determined in the first week of P. chabaudi infection [18]. In chronic infection, and for a period after exposure to long-lasting infection, Tcm can continue to generate Tem. Populations that protect best are marked by green asterisks, and populations that survive best are marked by red asterisks.