IL-7 enhances peripheral T cell reconstitution after allogeneic hematopoietic stem cell transplantation
Önder Alpdogan, Stephanie J. Muriglan, Jeffrey M. Eng, Lucy M. Willis, Andrew S. Greenberg, Barry J. Kappel, Marcel R.M. van den Brink
Önder Alpdogan, Stephanie J. Muriglan, Jeffrey M. Eng, Lucy M. Willis, Andrew S. Greenberg, Barry J. Kappel, Marcel R.M. van den Brink
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IL-7 enhances peripheral T cell reconstitution after allogeneic hematopoietic stem cell transplantation

Abstract

We used clinically relevant murine allogeneic bone marrow transplantation (BMT) models to study the mechanisms by which IL-7 administration can improve posttransplant peripheral T cell reconstitution. After transplant we could distinguish two populations of mature donor T cells: (a) alloreactive T cells with decreased expression of CD127 (IL-7 receptor α chain) and (b) nonalloreactive T cells, which express CD127 and undergo homeostatic proliferation. IL-7 administration increased the homeostatic proliferation of nonalloreactive T cells, but had no effect on alloreactive T cells and the development of graft-versus-host disease. Allogeneic transplant of purified hematopoietic stem cells and adoptive transfer of thymocytes into lethally irradiated hosts suggested that recent thymic emigrants can undergo homeostatic proliferation and acquire a memory-like phenotype. We found by BrdU pulse-chase, cell cycle, and annexin V analyses that IL-7 administration has significant proliferative and antiapoptotic effects on posttransplant peripheral T cells. We conclude that homeostatic expansion is important for T cell reconstitution after allogeneic BMT and involves both transferred mature T cells and recent thymic emigrants. Apart from its thymopoietic effects, IL-7 promotes peripheral T cell reconstitution through its selective proliferative and antiapoptotic effects on nonalloreactive and de novo–generated T cells, but has no effect on alloreactive T cells.

Authors

Önder Alpdogan, Stephanie J. Muriglan, Jeffrey M. Eng, Lucy M. Willis, Andrew S. Greenberg, Barry J. Kappel, Marcel R.M. van den Brink

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Figure 1

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T cell and B cell reconstitution after allogeneic BMT. (a and b) Lethall...
T cell and B cell reconstitution after allogeneic BMT. (a and b) Lethally irradiated (1,300 cGy) CBA/J recipients were transplanted with B10.BR TCD-BM (5 × 106) with or without B10.BR T cells (0.5 × 106) to induce GVHD. At different timepoints after BMT, animals were sacrificed and absolute numbers of donor-derived cell populations in the spleen were calculated from total cell counts and multicolor flow cytometric analyses of T cells with anti-CD3, -CD4, and -CD8 antibodies (a), and B cells with anti-B220 antibody (b). Donor or host origin was determined with anti-Ly9.1, which is present on host leukocytes. Allo, allogeneic. (c) The dot plots demonstrate how CD44high and CD44low T cells can be distinguished by flow cytometric analysis in the spleen of a normal mouse and that CD44low populations represent naive CD4+ T cells, which express CD62L, or naive CD8+ T cells, which do not express CD122. CBA/J mice were transplanted as described in Figure 1a without the addition of T cells, and splenocytes were analyzed on day 28. Naive CD4 cells were defined as CD4+CD44low, memory/activated (MEM/ACT) CD4 cells were defined as CD4+CD44high, naive CD8 cells were defined as CD8+CD44low, and memory/activated CD8 cells were defined as CD8+CD44high. (d) CBA/J mice were transplanted as described in Figure 1a without the addition of T cells and received 10 μg/day IL-7 or PBS (control) on days 21–27 by intraperitoneal injection. Splenocytes were analyzed at different timepoints after transplant. Values represent the mean cell number ± SEM (n = 6–20). *P < 0.05.