Abstract

The diverse host defense and immunoregulatory functions of human T cells are performed by phenotypically heterogeneous subpopulations. Among the membrane antigens that are differentially expressed by reciprocal human T-cell subsets are the CD45RA and CD45RO isoforms of the common leukocyte antigen family, which have been hypothesized to identify "naive" and "memory" T cells, respectively. The CD45RA antigen is first expressed by T-lineage cells relatively late during their intrathymic maturation and continues to be expressed by most T cells in the immunologically naive neonate. With increasing age and antigenic exposure, however, CD45RA-/RO+ cells become more prevalent in the circulation and comprise the majority of cells in tissues. Analyses of the functional capabilities of CD4+CD45RA+ and CD4+CD45RO+ cells have shown that proliferative responses to "memory" recall antigens or the ability to provide help for antibody production are functions uniquely performed by CD4+CD45RA-/RO+ cells. The major immunoregulatory functions described for CD4+CD45RA+ cells involve suppression of immune responses, either directly or via the induction of suppressor activity by CD8+ cells. Two general models of differentiation have been proposed to describe the lineal relationship of these T-cell subsets. Although these subsets could represent mature, phenotypically and functionally stable progeny arising from separate differentiation pathways, there is considerable experimental support for the hypothesis that CD45RA-/RO+ cells are "memory" cells that derive from "naive" or "virgin" CD45RA+/RO- precursors via an activation-dependent postthymic differentiation pathway. Altered frequencies of CD45RA+ and CD45RO+ T cells have been observed in a variety of different clinical conditions, particularly diseases manifesting altered immune function. These findings have contributed new information concerning the physiological events regulating the in vivo generation of these T-cell subsets. In addition, they may provide clues to the pathogenetic processes associated with certain diseases.