Peripheral T Cell Apoptosis Is Associated with Homeostatic T Cell Proliferation and Plays a Significant Role in Post-Transplant Immune Deficiency.

Post-transplant peripheral T cell apoptosis is an important (but ill-defined) contributor to the delay in T cell recovery after an allogeneic bone marrow transplantation (BMT). Using murine bone marrow transplantation (BMT) models to analyze post-transplant peripheral T cell apoptosis, we found that donor BM-derived T cells had a higher percentage of apoptotic cells, with decreased BCL-2 levels in young (3-month old) and old (20-month old) recipients of T cell-depleted (TCD) and T cell-repleted allogeneic BMT. Allogeneic recipients of donor BM deficient of Fas, BAX and TRAIL, or with overexpression of BCL-2 and AKT showed no decrease in donor-derived apoptotic T cells, suggesting that these molecules are not directly responsible for post-transplant peripheral T cell apoptosis. However, we noted that both CD4+ and CD8+ Memory T cells (CD44^high) exhibited increased apoptosis when compared to naive T cells post-BMT and therefore used RAG-2-eGFP transgenic mice to study whether T cell maturation affects peripheral T cell apoptosis. We found increased numbers of apoptotic cells in mature (eGFP^low) T cells compared to non-divided (eGFP^high) recent thymic emigrants in RAG-2-eGFP transgenic mice and in recipients of RAG-2-eGFP transgenic (Tg) BM. Interestingly, most of the apoptotic T cells were of eGFP^lowCD44^high memory phenotype in both CD4+ and CD8+ T cells, while eGFP^lowCD44^low naive T cells showed no sign of enhanced apoptosis. Moreover, we found similar increased levels of apoptosis of homeostatically proliferating T cells (CD44^high-memory-like cells) in recipients of lineage-depleted allogeneic RAG2-eGFP Tg BM or B6 BM. We then tested the effects of homeostatic T cell proliferation on peripheral T cell apoptosis in recipients of syngeneic CFSE-labeled T cells and found again increased levels of apoptosis in the fast proliferating populations of both CD4+ and CD8+ T cells. These cells expressed high levels of CD44 but down-regulated CD62L on their surface and in contrast to allogeneic proliferation exhibited low levels of CD25 expression and high level of IL-7Rα expression (75%). In addition, BCL-2 expression was down-regulated in the fast-proliferating cell population in both CD4+ and CD8+ T cells.

We conclude that newly generated donor BM-derived T cells have increased peripheral T cell apoptosis, which is associated with homeostatic proliferation and does not involve Fas, BAX, TRAIL, and AKT. This mechanism of peripheral T cell apoptosis, which has not been recognized previously, plays a significant role in post-transplant T cell deficiency and represents a promising target for novel strategies to overcome post-transplant immune deficiency in BMT recipients.