25 September 2002

by Donna Farber DFARBER@smail.umaryland.edu
 

Immunological memory provides cellular recall for the rapid and efficient mobilization of immune forces against pathogens previously encountered. During a primary immune response to new pathogens or antigens, naive T cells become activated, undergo proliferative expansion, and differentiate into effector cells. Although most activated/effector cells die after antigen is cleared, a proportion of these primed cells persist as memory T cells. The identity and functional properties of the activated/effector cells that perish versus those that survive as memory T cells are not known. Moreover, it is not known whether the two types of effector CD4 T cells, IFN-gamma-producing Th1 cells and IL-4 producing Th2 cells, have similar capacities for memory generation.

Seder and colleagues have begun to address these longstanding questions regarding memory T cell generation in a recent intriguing study. Using a combination of cytokine capture techniques and in vivo adoptive transfers, Wu, et al. demonstrate that the persisting memory T cell population derives from activated cells that are not producing the cytokine IFN-gamma. For their experiments, the authors generated antigen-specific Th1 effector cells in vitro or in vivo from DO11.10 mice expressing a transgenic T cell receptor specific for ovalbumin and MHC Class II. They sorted the resultant Th1 population into IFN-gamma⁺ and IFN-gamma- cells and transferred these subsets in vivo to unmanipulated, syngeneic mouse hosts. Several days post-transfer, they were able to detect persistence of both IFNgamma⁺ and IFN-gamma- transferred cells; however, after one week in vivo, the IFN-gamma⁺ cells literally disappeared from lymphoid and lung tissue, whereas IFN-gamma- cells persisted. Although the investigators did not examine other tissues that might serve as reservoirs for activated T cells, such as the lamina propria of the gut, these results strongly suggest that the precursors to long-lived memory T cells reside in the IFN-gamma- fraction of activated cells. Once cells have differentiated fully to produce IFN-gamma, they cannot convert to long-lived memory T cells.

Interestingly, the authors mention that this survival dichotomy between cytokine producers and non-producers does not occur with Th2 cells, where IL-4⁺ and IL-4^- fractions have similar survival potentials in vivo. Thus, development of memory depends critically on the type of response, the cytokines produced, and the differentiation state of activated cells. These findings have profound implications for vaccine design, where it might be advantageous to establish conditions that do not promote full differentiation to Th1 effector cells, to optimally promote a long-lived memory response.