Bone marrow function. I. Peripheral T cells are responsible for the increased auto-antiidiotype response of older mice.

Abstract

Recently (1) we have shown that, with age, there are changes in B cell clonal expression as manifested by differences in the idiotypes (Id) produced and an increase in the magnitude of the auto-anti-Id response. The increased auto-antiId response can be transferred to young recipients with splenic lymphoid cells from aged animals (2). However, lethally irradiated mice reconstituted with bone marrow (BM) from aged donors behave like young mice in that they manifest only modest auto-anti-Id responses (2), suggesting that the BM of old and young animals is similar. Furthermore, it has been shown that splenic T cells obtained from old mice modify the response of BM-reconstituted irradiated mice to behave in a manner typical of old animals with respect to auto-anti-Id production (2). On the basis of these observations we have proposed the hypothesis that the changes in Id expression and auto-anti-Id production in old animals are due to shifts in clonal distribution among the long-lived peripheral T cells, as a consequence of life-long interactions with internal and environmental antigens. This hypothesis predicts that if the peripheral lymphoid system of an old animal is acutely depleted of cells while the BM is left intact (e.g., irradiation with BM shielding) and the animals are allowed to repopulate their peripheral lymphoid system from their own marrow, they should behave like young mice with respect to auto-anti-Id production and it should be possible to influence this pattern of recovery transfer of peripheral T cells from donors of different ages. These predictions are borne out by the present results. Materials and MethodsAnimals, Irradiation, and Cell Transfer. C57BL/6J male mice were used. Old animals were 18 mo old, or older, while young mice were 8 wk old. Mice were anesthesized with tribromo ethanol, and placed in a lead shield that protected the bone marrow of their rear legs, head, and part of their spinal column, while permitting irradiation of their This work was supported in part by grants AG00842, Aii i 694, AG04860, AG00541, and AG00239 from the National Institutes of Health. J. Exe. MEt).

Old mice recover the ability to produce IgG and high-avidity antibody following irradiation with partial bone marrow shielding.

“…These data were consistent with the hypothesis that long-lived peripheral T cells serve as a repository for memory of life-long interactions with self and environmental antigens and that these peripheral T cells shift the clonal distribution of B cells arising from the bone marrow. These conclusions, initially derived from cell-transfer studies, have been confirmed in experiments with the autoreconstituted mouse model (5).…”

“…It appears that the age-associated changes in these characteristics of the primary immune response of old animals to antigen are determined by the peripheral T-cell population. We have obtained (5) evidence that hapten-augmentable PFCs are cells whose secretion of antibody is reversibly inhibited by the binding of anti-Id autoantibody to cell surface immunoglobulin. If the curves for hapten inhibition of plaque formation are calculated from the maximum number of PFCs detected in the presence of low concentrations of hapten rather than from the number of PFCs in the absence of hapten, then one can estimate the avidity distribution of the total population of TNP-specific B cells, including those whose secretion had been inhibited by the binding of anti-Id autoantibody.…”

“…The increased anti-Id autoantibody response of old animals reflects changes in the peripheral B-cell population. The bone marrow of aged and young mice are comparable with respect to their capacity to generate anti-Id autoantibodies in young, lethally irradiated recipients (4,5). Furthermore, if peripheral lymphoid cells of old mice are depleted by irradiation while their bone marrow is partially shielded, then, after recovery from irradiation, the autoreconstituted old mice respond with a young-like, low, anti-Id autoantibody response following primary immunization (5).…”

Aging and the Immune Response

“…Szewczuk and Campbell (1980) have also found evidence for a strong influ ence of anti-Id antibodies on B-cell respon siveness in old mice. Generation of these regulatory, anti-idiotypic antibodies seems to depend on the presence of T cells from old mice, in that animals allowed to reconstitute their own immune systems from protected limb bone marrow after ir radiation produce such antibodies only if inoculated with T cells from old mice dur ing the repopulation interval (Kim et al, 1985); the presence of aged T cells during the period of autoreconstitution also leads to mice that, like old controls, produce antibodies of lower affinity and higher IgM/IgG ratios (Tsuda, Kim, Siskind, & Weksler, 1988).…”

Age-Associated Changes in Antibody-Forming Cells (B Cells)

“…and bone marrow reconstituted the periphery together with T cells from young or aged donors. It was found that mice that received young T cells displayed auto-anti-idiotypic antibody profiles and a response to TNP-F like that of the young donor (61,62), whereas those that received aged T cells responded like the aged donors (61,62). These results strongly implicate the T cells in the quantity and quality of the immune response.…”