ALLOGENEIC BONE MARROW INHIBITS T-CELL ACTIVATION AND CLONAL EXPANSION IN VITRO1

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Abstract
Donor bone marrow infusion has long been used to enhance graft survival or induce tolerance in T cell depleted solid organ allograft recipients. However, the mechanisms through which bone marrow cells affect tolerance remain obscure. We studied the affect of allogeneic bone marrow cells on the activation of allospecific T cells in vitro. Carboxyfluorescein-diacetate succinimidyl ester-labeled CBA/Ca strain CD8+ splenocytes, bearing T-cell receptor alpha and beta transgenes from the BM3.3 T-cell clone specific for the major histocompatibility complex class I antigen Kb, were placed in culture with irradiated C57BL/6J stimulator cells in the presence of increasing numbers of C57BL/6J or Balb/cJ bone marrow cells for 1 to 3 days. Responder cells were individually analyzed for proliferative history, expression of activation-associated antigens, and intracellular cytokine production. Allogeneic bone marrow cells exert a dose-dependent inhibitory effect on proliferation of allospecific CD8+ T cells in mixed lymphocyte culture. However, the inhibited T-cell subpopulations show physiologic changes associate with the early stages of T-cell activation, including expression of CD69 and early decrease of surface T-cell expression. Unlike cells not co-cultured with bone marrow, these cells fail to reexpress the T-cell receptor (TCR) by 72 hr of culture. The observed inhibitory effect is also associated with a decrease in the proportion of CD8+ cells expressing interleukin-2 and interferon-gamma. Collectively, these results suggest that peripheral allospecific T cells undergo the initial stages of activation on exposure to antigen in the presence of bone marrow cells, but the cell cycle is arrested and TCR reexpression is inhibited. We speculate that bone marrow cells effect this inhibition through a receptor-ligand interaction that modulates the transmembrane signal pathway for the TCR.