Immunoregulation in senescence: increased inducibility of antigen-specific suppressor T cells and loss of cell sensitivity to immunosuppression in aging mice.

Abstract

Azobenzenearsonate (ABA)-specific T cell-mediated suppression has been studied in aging mice. ABA-specific suppressor T cells were induced in young and old mice by injection ofABA conjugated to syngeneic spleen cells (ABA-SC). These suppressor cells were tested for their ability to suppress the in vitro anti-trinitrophenyl (TNP) antibody response of lymph node cells obtained from ABA-keyhole limpet hemocyanin (KLH)-primed young or old mice and cultured with TNP-ABA-KLH. Suppressor T cells were found to be more easily induced in old than in young mice but to suppress less efficiently the antibody response of cells from old than from young mice. The increased inducibility of antigen-specific suppressor T cells in old mice is compatible with the age-dependent decline of immune responsiveness to exogenous antigens. The loss of cell sensitivity to antigen-specific immunosuppression as well as the lack of evidence for increased nonspecific suppression in old mice is consistent with the age-related increase in autoimmune disorders. These findings provide a unifying explanation for the most relevant immunological phenomena of senescence.Immunologic mechanisms are involved to a large extent in the biologic processes of aging, as reviewed by Walford (1). The maximal lifespan, which appears to be regulated by a finite set of genes (2), is significantly influenced by the major histocompatibility complex (3), which plays a fundamental role in the genetic control of immunologic functions (4). Morphologic, functional, and pathologic alterations occurring in aging animals are associated with both progressive decline of immune responsiveness to exogenous antigens and increasing incidence of autoimmune phenomena (5).The decline of immune responsiveness results mostly from alterations of lymphoid cell populations rather than from changes in the animal milieu during senescence (6). Number and activity of macrophages seem to be unaffected by aging (7-9). Most reports indicate no or only a slight decrease in lymphocyte number but profound functional defects in B cell and helper T cell populations during senescence (10-17). The decrease in helper activity has been attributed to thymus involution (18) and subsequent reduced concentration ofthymic factors (19-21) involved in the differentiation ofprecursor cells into functionally mature T cells (22).The incidence of autoantibodies in mice and men shows a dramatic increase with age (23). The B cell resistance to tolerance induction to foreign antigens in old mice (24), the increased level ofT cells binding autologous erythrocytes in old mice (25) and men (26), and the increased response of old mice to chemically altered syngeneic erythrocytes (27) underlie an enhanced propensity to lose self-tolerance during senescence. Age-dependent changes in the capacity to maintain self-tolerance have also been suggested by the higher efficiency of polyclonal activators, such as lipopolysaccharide, to stimulate an autoantibody response against syngeneic erythrocytes in old mice. Because poly...

Deficiency in suppressor T cell activity in aged animals. Reconstitution of this activity by interleukin 2.

“…It is clear that in the experimental set-up used in this report, suppressor cells from aged cells are deficient in their expansion during a 3-5-d period in vitro, and that lymphokine preparations containing IL-2 restore this function. In this respect our results are reminiscent of others (8,9) that demonstrate that splenocytes from aged animals are not as effectively stimulated by concanavalin A to become suppressor cells as are cells from young adult animals. This may also reflect the relative inability of aged cells to produce IL-2 and/or other lymphokines upon stimulation with mitogens.…”

Accessory Function and Properties of Monocytes from Healthy Elderly Humans for T Lymphocyte Responses to Mitogen and Antigen

“…Lymphocytes from elderly subjects are defec tive in blastogénie responses to such stimuli [4][5][6][7] although the response to anti-CD3 is controversial [7], Studies of the basis for the depressed responses to nonspecific mitogens have focused on the T lymphocyte itself and found, for example, a defect in the production of [8][9][10] and response to [11] interleukin (IL)-2, and in the expression of IL-2 receptors by lymphocytes [10,11]. The number of mito gen-responsive T lymphocytes from the el derly is reduced [12] and 25% fewer T lym phocytes from elderly subjects enter and transit through the cell cycle [13].…”

Thymosins, Lymphokines, and the Immunology of Aging

“…mixed lympho cyte reactions (MLR), antibody production, cytotoxic T cells (CTL), and autologous re sponses [9,10,12,36, 42,57], This mal functioning of the immune response with aging has been attributed to a combination of factors, including loss of T helper cells, increase in suppressor cells [1,3,5,7,9,10,19,36,64], and loss of T progenitor cells in the bone marrow [59]. The decline of im mune function with age is complex, involv ing changes in multiple lymphocyte subsets as well as the regulation of cell-cell interac tions.…”