title: Enhancing alloreactivity does not restore GVHD induction but augments skin graft rejection by CD4⁺ effector memory T cells.
abstract: Graft-versus-host disease (GVHD) caused by donor T cells attacking recipient tissues is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (alloSCT). Studies have shown that effector memory T (T(EM) ) cells do not cause GVHD but are capable of immune functions post-transplant, including graft-versus-leukemia (GVL) effects, but the reasons for this are unclear. In mice, the T(EM)  pool may have a less diverse T-cell receptor (TCR) repertoire than naive T (T(N) ) cells with fewer alloreactive clones. We therefore tested whether enhancing the alloreactivity of T(EM)  cells would restore their ability to cause GVHD. In an MHC-matched system, alloreactive T(EM)  cells were created by transferring GVHD effector cells into syngeneic recipients and allowing conversion to T(EM)  cells. Upon retransfer to freshly transplanted recipients, these cells caused only mild GVHD. Similarly, in an MHC-mismatched system, T(EM)  cells with a proven increased precursor frequency of alloreactive clones only caused limited GVHD. Nonetheless, these same cells mounted strong in vitro alloresponses and caused rapid skin graft rejection. T(EM)  cells created from CD4(+)  T cells that had undergone lymphopenia-induced proliferation (LIP) also caused only mild GVHD. Our findings establish that conversion to T(EM)  cells significantly reduces GVHD potency, even in cells with a substantially enhanced alloreactive repertoire.
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520-8035, USA.
authors.forename: Britt E
authors.initials: BE
authors.lastname: Anderson
authors.forename: Anita L
authors.initials: AL
authors.lastname: Tang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Monica
authors.initials: M
authors.lastname: Froicu
authors.forename: David
authors.initials: D
authors.lastname: Rothstein
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: McNiff
authors.forename: Dhanpat
authors.initials: D
authors.lastname: Jain
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Demetris
authors.forename: Donna L
authors.initials: DL
authors.lastname: Farber
authors.forename: Warren D
authors.initials: WD
authors.lastname: Shlomchik
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shlomchik
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D004195:Disease Models, Animal; D019672:Genes, T-Cell Receptor / Q000235:genetics; D006084:Graft Rejection / Q000235:genetics; D006086:Graft vs Host Disease / Q000209:etiology* / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D011183:Postoperative Complications; D016038:Skin Transplantation; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation
chemical_list: D007519:Isoantigens