Control of CD4+ T-cell memory by cytokines and costimulators

Summary: During T‐cell priming, cytokines and costimulatory molecules provide important signals that determine the magnitude and quality of the response. Although the functions of defined cytokines and costimulators in the primary T‐cell response are well characterized, much less is known about how these factors contribute to memory T‐cell development and survival. Since memory cells are thought to be long‐lived progeny of the primary response, it is conceivable that the same signals shaping initial T‐cell expansion and differentiation also contribute to memory generation. Here, we review evidence and show novel data on the role of the cytokines interleukin‐2 (IL‐2) and IL‐7 and the costimulator CD28 in CD4⁺ memory T‐cell development. We emphasize that transient IL‐2 and CD28 signals during priming imprint a long‐lasting survival advantage in primed T cells, thus contributing to the persistence of a memory population. The requirement for IL‐2 and CD28 signals is not linked to promoting T‐cell division and expansion but most likely due to their capacity to (i) promote effector cell differentiation; (ii) induce survival proteins, and, as we discuss in more detail; (iii) program expression of receptors for ‘memory survival factors’ such as IL‐7. Studies exploring the therapeutic potential of these insights are also discussed.