title: Total lymphoid irradiation nonmyeloablative preconditioning enriches for IL-4-producing CD4+-TNK cells and skews differentiation of immunocompetent donor CD4+ cells.
abstract: Preconditioning with the nonmyeloablative regimen total lymphoid irradiation (TLI) before hematopoietic cell transplantation facilitates the establishment of mixed chimerism and protects against graft-versus-host disease. We reported that the development of mixed chimerism requires interleukin (IL)-4 and is associated with increased host anti-donor TH2 cells, but the effect of TLI on the differentiation of immunocompetent donor cells has not been investigated. To examine the extent to which TLI preconditioning influences donor T cells, we measured responses of transgenic CD4+cells specific for ovalbumin peptide (OVA-Tg) following in vivo and in vitro antigen stimulation in a TLI-preconditioned environment. OVA-Tg cells that were adoptively transferred into TLI-preconditioned mice that express cross-reactive antigens produced more IL-4 and less interferon-gamma and IL-2 than controls when stimulated with OVA peptide one week later. OVA-Tg primed in vitro with spleen from TLI-preconditioned mice generated more TH2 and fewer TH1 cells when stimulated in recall enzyme-linked immunosorbent spot (ELISPOT) assays with OVA peptide. Naive OVA-Tg up-regulated CD69 and CD25 normally following stimulation with OVA peptide in the presence of spleen from TLI-preconditioned mice, but proliferated less and secreted less IL-2 than controls. Surprisingly, naive OVA-Tg secreted 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 composed primarily of CD4+-natural killer T (TNK) cells. Thus, TLI preconditioning enriches for IL-4-secreting and TNK-like CD4+cells that may function in the protection from graft-versus-host disease by redirecting the differentiation of immunocompetent donor CD4+cells toward TH2 and away from pathogenic TH1 cells.
authors.affiliation: Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52246, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Rigby
authors.forename: Todd
authors.initials: T
authors.lastname: Rouse
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Field
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation; D005786:Gene Expression Regulation / Q000528:radiation effects; D007108:Immune Tolerance / Q000276:immunology; D007156:Immunologic Memory; D015847:Interleukin-4 / Q000096:biosynthesis / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology; D037181:Lectins, C-Type; D015182:Lymphatic Irradiation; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D011828:Radiation Chimera; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D019172:Transplantation Conditioning; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015847:Interleukin-4; D037181:Lectins, C-Type; D010047:Ovalbumin; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D000099192:CD69 Antigens