Thymus is required for T cell reconstitution following lymphoablation

Lymphoablation is used as induction therapy in transplantation. Following lymphoablation, peripheral lymphopenia triggers homeostatic T cell proliferation and thymopoiesis. However, the relative contribution of each pathway to T cell recovery is unknown. The goal of this study was to test the role of thymus during T cell reconstitution following lymphoablation. We use a mouse model of heterotopic heart transplantation (BALB/c to B6) and a murine analog of Thymoglobulin (mATG). We previously reported that the recovery of CD8 T cells after mATG depletion requires residual memory CD4 T cells and CD40 expressing B cells. CD4 T cell depletion or CD154 blockade significantly reduced the numbers of single positive CD8 thymocytes generated in mATG treated mice. To test if thymus is required for T cell reconstitution, thymectomized and euthymic heart allograft recipients were treated with mATG on days 0 and 4. Thymectomy impaired recovery of CD4 and CD8 T cells compared to euthymic mice (10% vs. 1.7% CD4 and 3% vs 0.06% CD8 T cells on d 12). The transplantation of thymi from B6 WT or RAG1−/− mice under the kidney capsule of thymectomized mice partially restored T cell reconstitution following depletion. Adoptive transfer of CD4 T cells (10×10 6 i.v. d −1) or treatment with agonistic anti-CD40 mAb (0.1mg i.v. d 0, 2) also restored T cell recovery in thymectomized mice. These results indicate that depletion-resistant memory CD4 T cells and thymus are both required for effective CD8 T cell recovery. Our findings may lead to therapies that specifically target reconstitution of naive vs memory T cells following lymphoablation.