Physical, biologic, and phenotypic properties of natural regulatory cells in murine bone marrow

Abstract

A lymphocyte-enriched fraction of murine bone marrow (BML) contains natural regulatory cells (NRC) that can inhibit, on a dose-dependent basis, proliferative and cytotoxic responses to alloantigens in a mixed lymphocyte culture. The objective of this study was to investigate the characteristics of the cells responsible for this phenomenon in CBA mice. Maximal suppression was obtained with BML cells themselves rather than cell products. Light-scatter analysis of NRC on the fluorescence-activated cell sorter demonstrated them to be larger than small lymphocytes, and their sedimentation in discontinuous Percoll gradients showed the cells to be of heterogeneous density. This heterogeneity is further reflected by the fact that both plastic adherent and nonadherent BML are suppressive. NRC must be viable in order to mediate suppression; they are cortisone-resistant and are not affected by doses of gamma irradiation up to 1,000 R. NRC are not T or B lymphocytes or Ia-bearing macrophages. The involvement of mature granulocytes and macrophages in natural suppression is unlikely in that NRC do not bear Fc receptors. Elimination of cells from BML with the natural killer (NK) surface marker Asialo GM1 does not abrogate suppression. NRC are capable of mediating suppression across major and minor histocompatibility complex barriers. While lymphoid cells are prominent in BML, the contamination of this marrow fraction with immature granulocytes and monocytes makes a morphologic identification of NRC difficult. These characteristics are most consistent with NRC begin immature marrow cells of undetermined lineage. The relationship of NRC to naturally occurring marrow suppressor cells described in other systems is not yet clear and awaits experimental clarification.

In vivo administration of interleukin 2 plus T cell-depleted syngeneic marrow prevents graft-versus-host disease mortality and permits alloengraftment.

“…Our data suggest that activation or generation by IL-2 of a cell population contained in TCD syngeneic marrow, such as lymphokine-activated killer (LAK) cells (23)(24)(25), NS cells (23,26), or veto cells (23,27), might play a role in protecting from GVHD mortality. Both NK and LAK cells have been shown to be activated by treatment with IL-2 in vivo (28)(29)(30)(31).…”

Characterization of Natural Suppressor Cells in Human Bone Marrow

“…Natural suppressor (NS) activity is defined as the ability of unprimed cells to exert nonspecific suppression in various immunological responses [1,2]. NS cells show "null" surface phenotype and have been identified at the site of active hematopoiesis, including bone marrow (BM) [3][4][5][6][7], neonatal spleen [8,9] and the spleen of mice after total lymphoid irradiation [1,10,11] or administration of Strontium 89 [12,13]. These findings suggest that hematopoietic progenitor cells exert NS activity in BM.…”

Bone Marrow-Derived Conventional, But Not Cloned, Mesenchymal Stem Cells Suppress Lymphocyte Proliferation and Prevent Graft-Versus-Host Disease in Rats

“…Natural suppressor cell activity is defined as the ability of unprimed effector cells to suppress the response of lymphocytes to immunogenic and mitogenic stimuli without MHC restriction (34,42). These cells have been found in mouse (16), rabbit (46), and human BM (32). The lineage of natural suppressor cells remains controversial.…”