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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-05-1513.
Submitted May 23, 2002
Accepted October 14, 2002
Total lymphoid irradiation nonmyeloablative preconditioning enriches for IL-4 producing CD4+-TNK cells and skews differentiation of immunocompetent donor CD4+ cells
Shawn M Rigby, Todd Rouse, and Elizabeth H Field*
Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA
Department of Veterans Affairs Medical Center, Iowa City, IA, USA
* Corresponding author; email: elizabeth-field{at}uiowa.edu.
Preconditioning with the nonmyeloablative regimen total lymphoid irradiation (TLI) prior to hematopoietic cell transplant facilitates the establishment of mixed-chimerism and protects against graft-vs-host-disease. We reported that the development of mixed-chimerism requires IL-4 and is associated with increased host anti-donor Th2 cells, but the effect of TLI on the differentiation of immunocompetent donor cells had not been investigated. To examine the extent to which TLI preconditioning influences donor T cells, we measured responses of OVA-transgenic CD4+ cells (OVA-Tg), following in vivo and in vitro antigen stimulation within a TLI-preconditioned environment. OVA-Tg cells that were adoptively transferred into TLI-preconditioned mice that express cross-reactive antigens produce more IL-4 and less IFN and IL-2 than controls when stimulated with OVA-peptide one week later. OVA-Tg primed in vitro with spleen from TLI-preconditioned mice generate more Th2 and less Th1 cells when stimulated in recall ELISPOTs assays with OVA-peptide. Naive OVA-Tg upregulate CD69 and CD25 normally following stimulation with OVA-peptide in the presence of spleen from TLI-preconditioned mice, but proliferate less and secrete less IL-2 than controls. Surprisingly, naive OVA-Tg secrete IL-4 in primary cultures that were stimulated with OVA-peptide in the presence of spleen from TLI-preconditioned mice. This response depends on CD4+ cells from TLI-spleen, which constitutively produce IL-4 and are comprised primarily of CD4+-TNK cells. Thus, TLI-preconditioning enriches for IL-4 secreting and TNK-like CD4+ cells that may function in the protection from graft-vs-host-disease by redirecting the differentiation of immunocompetent donor CD4+ cells towards Th2 and away from pathogenic Th1 cells.
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