Effector memory CD4+ T cells (Tem) are important for protection from many chronic infections, but their development is poorly understood. While IFN-γ+ effector T cells (Teff) can survive into the memory phase in infection, it is not clear if mature Teff generate Tem, or if memory T cells diverge from Teff early after activation, as suggested for central memory T cells (Tcm) by data in model antigen systems. However, we have shown that both Tem and Teff are continuously generated from Tcm in chronic malaria infection. In the current study, we identified phenotypic subsets defining the gamut of activation of Teff using malaria-specific B5 TCR transgenic and IFN-γ reporter mice. We demonstrate that all Effector subsets (Early, Middle and Late) divide, and make IFN-γ in Plasmodium chabaudi infection, with IFN-γ+ TeffMid dominating expansion. We have shown by adoptive transfer that only TeffEarly have the potential to differentiate into the Middle and Late subsets, while TeffMid express low levels of anti-apoptotic Bcl-2, and high levels of Fas and PD-1, suggesting terminal differentiation. TeffLate express high levels of the Th1 factors T-bet and RUNX3, but are highly apoptotic. Of these subsets, only the less-differentiated TeffEarly subset survives to become memory cells (both Tcm and Tem) in naïve recipients. Our data suggest that TeffEarly are the elusive CD4+ precursor to memory and will accelerate the study of T cell mediated vaccine protection from the earliest stages.
- Copyright © 2013 by The American Association of Immunologists, Inc.