Unidirectional development of CD8+ central memory T cells into protective Listeria-specific effector memory T cells

Abstract

Three distinct subsets of antigen-experienced CD8(+) T cells have been identified so far: short-living effector T cells (T(EC)) and two long-living subsets, described as central (T(CM)) and effector memory (T(EM)) T cells. The lineage relationships of these subpopulations as well as their involvement in protection have not yet been conclusively determined. We recently described a novel marker combination (CD127 and CD62L) to identify all three major CD8(+) T cell subsets in mice infected with Listeria monocytogenes (L.m.). Extensive lineage relationship analyses on highly purified subpopulations after in vitro and in vivo stimulation demonstrated that T(CM) can develop into T(EM) or T(EC), whereas T(EM) can only progress to T(EC) cells. Short-living T(EC) never regained a T(EM) or T(CM) phenotype. These data strongly suggest a hierarchical and unidirectional order of developmental stages. In vivo priming protocols that preferentially induced one of the different CD8(+) T cell subsets demonstrated that predominance of T(EM) (CD40 stimulation) correlated best with effective protection against L.m., whereas generation of neither T(CM) (by immunization with heat-killed L.m.) nor T(EC) (by systemic co-administration of CpG during primary infection) conferred substantial long-term protective immunity. These findings have important implications for the design of more effective T cell-based vaccines.