The ability of lymphoid cells from immunized animals to regulate the response of naive B ceils to the immunizing hapten was studied. Mice were immunized with trinitrophenylated (TNP) bovine gamma globulin (BGG) in complete Freund's adjuvant, and their spleen cells were examined in vivo and in vitro for the presence of specific inhibitory activity. This activity was found to peak 1 wk after immunization, was active against TNP on both T-dependent (BGG) and T-independent (Ficoll and polyacrylamide beads) carriers, and was demonstrable both by mixed cell transfers and mixed cell culture experiments. In in vitro studies, it was shown that the inhibition of the response to TNP- polyacrylamide beads by immune spleen cells was mediated by a non-T cell, possibly a B cell, because the suppressor activity was enriched in a purified B cell preparation. A role for macrophages was not formally ruled out. A specific suppressor factor was produced in vitro by immune spleen cells cultured in the absence of antigen. The suppressor activity was modulated by T .cells because elimination of T cells from the normal spleen cell population decreased suppression; elimination of T cells from the immune spleen cell population did not effect suppression, but elimination of T cells from both the normal and immune spleen cell populations allowed the expression of marked specific suppression. Thus, T cells present in the normal spleen cell population augment the degree of suppression, whereas T cells present in the immune spleen cell population decrease the degree of suppression; that is, T cells present in the immune spleen cell population had the ability to specifically abrogate suppression ("abrosuppression") in a T-independent immune response. It is proposed that the response to a T- independent antigen is regulated by specific suppressor activity generated by a non-T cell and augmented by the interaction of this cell with a T cell. The suppressor activity can be blocked by a specific abrosuppressor T cell. It is suggested that, because suppressor activity appears dominant in the naive state of the immune system, the induction of specific abrosuppressor activity may be essential if an immune response is to take place.
SUMMARY We have identified two types of clones responsive to Mls determinants. One type responded vigorously to purified B cells from mice bearing Mlsa‐stimulatory determinants. The other type, including clone Lyl‐N5, responded vigorously to unfractionated spleen cells, but failed to respond to B cells alone or to spleenadherent cells (SAC) alone from the Mlsa‐bearing mice. Synergy between two stimulator cell types, B cells and SAC, was required to induce the Mls response of clone Lyl‐N5. The failure of clone Lyl‐N5 to respond to Mlsa‐bearing B cells was reversed by the addition of SAC taken from mice bearing the Mlsb allele or the non‐stimulatory Mlsb allele. B cells were required to provide the Mlsa determinant. The Mls response of clone Ly1‐N5 is restricted by class II determinants shared by the H‐2b, H‐2d and H‐2k haplotypes, but not the H‐2q haplotype. The optimal response of the clone was obtained by using B cells bearing both Mlsa and the permissive H‐2 alloantigen. However, complementation was also observed between B cells bearing Mlsa and the non‐permissive Iaq and SAC bearing the non‐stimulatory Mlsb, but a permissive la epitope, resulting in activation of the clone. Clone Ly1‐N5 responds to Mlsa‐bearing B cells only in the presence of SAC. The SAC provide an undefined signal required for the proliferation of certain clones such as clone Ly1‐N5, which is not provided by normal B cells. In this report, we show that the AKTB‐lb B‐cell tumour line stimulates the proliferation of clone Ly1‐N5, in the absence of SAC, suggesting that the tumour line has acquired the capacity to provide this signal.
Inducer/helper T cells recognize nominal antigen in association with Ia on the surface of the antigen-presenting cell (APC). Recent studies have shown that B cells can effectively function as APC. In the present study we have assessed the ability of cloned inducer T cells to discriminate between activated B cells or splenic macrophages as APC. We found that most of the clones tested demonstrated an equivalent response to antigen presented by activated B cells or splenic adherent cells. Some clones were very efficiently stimulated by antigen presented by activated B cells, whereas other clones failed to respond or responded very poorly when activated B cells were used to present antigen. We attempted to determine the mechanism responsible for the inability of certain clones to proliferate in response to antigen presented by activated B cells.
Graft-versus-host disease (GVHD) continues to be a common cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The T cell immunoglobulin and mucin (TIM) proteins represent a family of molecules that act in concert with T–cell receptor and costimulatory signals to regulate expansion, differentiation and effector function of T and NKT cells. TIM-1 binds to phosphytidylserine, exposed on the surface of apoptotic cells. Given the immunoregulatory role of TIM-1, we explored how TIM-1 influences GVHD in a murine model of allogeneic HSCT which causes massive apoptosis. Here we show that mice treated with an antagonistic anti-TIM-1 mAb that blocks phosphatidylserine recognition are protected from lethal GVHD. Protection against GVHD appears to be mediated by TIM-1 expression on the donor graft as TIM-1 knockout mice showed minimal survival advantage after allogeneic HSCT. Mice treated with anti-TIM-1 mAb cleared the A20 tumor cells suggesting that GVL effects are preserved. By bioluminescent imaging, it was determined that TIM-1 blockade does not alter the homing and expansion of donor T cells in vivo, nor does it affect T or NKT cells proliferation in vitro. Moreover, using microarray analysis, we found that anti-TIM-1 treatment protects from lethal GVHD by promoting an anti-inflammatory environment in the gut tissue. Antagonistic anti-TIM-1 mAb also protects from lethal GVHD in a xenogeneic model of GVHD. Overall, these findings can form the basis for the development of novel therapeutic strategies to prevent GVHD and improve HSCT.
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