Graft-versus-Host Disease Output during Experimental Circles as Molecular Markers for Thymic On the Relevance of TCR Rearrangement

Efficient reconstitution of the pool of peripheral T cells after hemopoietic stem cell transplantation (HSCT) is dependent on normal thymic function. However, the development of graft-vs-host disease (GVHD) in the context of allogeneic HSCT is associated with injurious effects on thymocyte development. In this study, we examined in models of syngeneic and allogeneic murine HSCT whether actual posttransplant thymic output is accurately reflected by analysis of signal-joint TCR rearrangement excision circles (sjTRECs). Our data demonstrate that the de novo generation of T cells following syngeneic HSCT of T cell-deficient B6.RAG2 (recombination-activating gene 2 ؊/؊) mice correlates firmly with an increase of sjTRECs in the thymus and spleen. However, the altered homeostasis of naive peripheral T cells in the presence of GVHD necessitates the combined analysis of cell division in vivo and determinations of sjTREC contents and total sjTREC numbers to draw informative conclusions. From our data, we substantiate that thymic output and peripheral division of newly generated T cells are diminished in the presence of acute GVHD in an experimental radiation/allogeneic HSCT model. A llogeneic hemopoietic stem cell transplantation (HSCT) 3 is the preferred therapy for a number of life-threatening disorders. The success of allogeneic HSCT depends on the efficiency by which the host's immune system is restored (reviewed in Refs. 1–3). Unfortunately, the T cell lineage is not generated as rapidly and efficiently as most other hemato-logical lineages, a situation that invariably results in a protracted immune deficiency in the posttransplant period. Recent studies aimed at a better understanding of the regenerative mechanisms demonstrated that the donor-derived peripheral T cell pool is restored through two independent pathways: 1) expansion of adop-tively transferred mature T cells, and 2) intrathymic de novo generation of T cells from donor HSC (1–3). Although transfer of mature T cells during allogeneic HSCT may provide a short-term restoration of immune functions, a long-lasting and complete re-constitution depends ultimately on the new generation of T cells in the thymus (1, 2, 4 – 8). To this date, however, it has proven difficult to assess the precise extent to which thymic function contributes to the reconstitution of the immune system following al-logeneic HSCT. Indeed, different independent factors may influence thymic output following HSCT (2, 8 –10). One such parameter is graft-vs-host disease (GVHD). GVHD represents a major allogeneic HSCT-related complication (11, 12), and it exacerbates posttransplant T cell hypoplasia (13). Deficient T cell reconstitution as a consequence …