Promotion of Stem Cell-Derived New T Cell Generation by CD62L− Memory T Cells Requires Alloantigen Recognition.

Abstract

We recently demonstrated that non-GVHD-inducing CD62L− memory T cells promote T cell regeneration from hematopoietic stem/progenitor cells in the C57BL/6 (H2b) to BALB/c (H2d) bone marrow transplantation model (BLOOD 2004,103:1534). In this model, 1×107 T cell depleted bone marrow from C57BL/6, CD45.2, Thy1.2 mice and 1×106 CD62L− T cells from C57BL/6, CD45.1, Thy1.1 mice are used and the recipient mice are lethally irradiated. This animal model allows us to differentiate the T cells of different origin by flow cytometry. In the current study, we further investigated how CD62L− T cells promote new T cell generation and whether there is any functional relevance using the same model. Previous data suggest that the promoting effect of CD62L− T cells on stem cell-derived new T cell generation is associated with the facilitation of engraftment because host radioresisdant T cells were depleted in CD62L− T cell recipients but not in the T cell-depleted bone marrow control mice. To determine whether CD62L− T cells promote new T cell generation by overcoming T cell-mediated host resistance, we performed the experiment using SCID mice as recipients. SCID mice lack both T and B cells. In consistent with the previous results, serial peripheral blood T cell counts following bone marrow transplantation demonstrated that the promoting effect of CD62L− T cells were dramatically decreased in the SCID recipients, indicating that CD62L− T cell promote new T cell regeneration by overcoming host resistance. To examine whether CD62L− T cells overcome host resistance by “veto effect”, we performed the experiment using CD62L− T cells from (BALB/cxC57BL/6)F1 mice. T cells from F1 mice do not recognize the parental recipient as non-self and can not initiate classical T cell response against the parental antigens. It was previously reported by other investigators that T cells from F1 mice preserve “veto effect”. However, no promoting effect was observed in the recipients of CD62L− T cells from the F1 mice, demonstrating that “veto effect” is not involved. Rather, alloantigen recognition by donor CD62L− T cells is required for the promoting effect. In agreement with the hypothesis that CD62L− T cells promote new T cell generation by enhancing engraftment through overcoming host resistance, both white cell and platelet recovery in peripheral blood was accelerated in CD62L− T cell recipients comparing with that in the control T cell-depleted bone marrow recipients. Finally, we sought to determine whether these findings have any functional relevance in vivo. We evaluated the functional immune recovery by measuring the ability to inhibit the growth of a recipient-type leukemia/lymphoma cell line called BCL1 cells injected intravenously into the transplantation recipients on day +7. While six out of eight T cell-depleted bone marrow control mice developed tumor and died within 30 days after bone marrow transplantation, none of the CD62L− T cell recipients (n=12) developed tumor and all survived more than 60 days after transplantation. As expected, none of the CD62L− T cell recipients developed graft-versus-host disease. Our data indicate that CD62L− T cells promote new T cell generation by enhancing engraftment through overcoming host resistance. This promoting effect requires alloantigen recognition and is not mediated by “veto effect”. Our current focus is trying to determine how allogeneic CD62L− T cells overcome host resistance without causing graft-versus-host disease.