T-cell P/E-selectin ligand alpha(1,3)fucosylation is not required for graft-vs-host disease induction.
OBJECTIVE
Recognition of E- and P-selectins on vascular endothelium by their leukocyte glycoprotein counterreceptor P-selectin glycoprotein ligand-1 (PSGL-1) initiates and sustains leukocyte rolling, culminating in extravasation of lymphocytes from blood into organs. PSGL-1 is rendered functional by terminal glycosylation steps, which occur mainly in activated Th1 but not Th2 cells. alpha(1,3)Fucosyltransferases IV and VII control this glycosylation pathway. Mice lacking these transferases (Fuc-TIV(-/-)/Fuc-TVII(-/-)) lack functional E- and P-selectin ligands. We hypothesized that Fuc-TIV(-/-)/Fuc-TVII(-/-) donor T cells might have reduced capacity to roll on vessels of inflamed target tissues and mediate graft-vs-host disease (GVHD).


METHODS
We compared the ability of Fuc-TIV(-/-)/Fuc-TVII(-/-) and wild-type (WT) C57BL/6 (B6) spleen cells (SPCs) to produce GVHD in lethally irradiated major histocompatibility complex (MHC) haplotype-mismatched B6D2F1 recipients. Clinical GVHD, GVHD pathology in target organs, memory phenotype conversion, proliferation of donor T cells, and tissue and serum cytokine expression were examined.


RESULTS
Surprisingly, clinical GVHD was not reduced in lethally irradiated mice receiving full haplotype MHC mismatched or matched Fuc-TIV(-/-)/Fuc-TVII(-/-) SPCs compared to those receiving WT SPCs. GVHD pathology in target organs, memory phenotype conversion, and proliferation of donor T cells were similar in both groups. However, reduced interferon-gamma was detected in liver and lung, and serum levels of tumor necrosis factor-alpha were higher in mice receiving Fuc-TIV(-/-)/Fuc-TVII(-/-) SPCs compared with WT SPCs.


CONCLUSIONS
These results suggest that donor T cells, including Th1, are capable of trafficking to GVHD target tissues independently of P- and E- selectin ligand in conditioned hosts.
Eom
Hyeon-Seok
HS
Transplantation Biology Research Center, Bone Marrow Transplantation Section, Massachusetts General Hospital/Harvard Medical School, Boston, 02129, USA.
Rubio
Marie-Therese
MT
Means
Terry K
TK
Luster
Andrew D
AD
Sykes
Megan
M
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D005260:Female; D005643:Fucose / Q000378:metabolism; D005647:Fucosyltransferases / Q000172:deficiency; D006031:Glycosylation; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology*; D006648:Histocompatibility; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009928:Organ Specificity; D017468:Receptors, Fibroblast Growth Factor / Q000276:immunology / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation
D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D017468:Receptors, Fibroblast Growth Factor; D012795:Sialoglycoproteins; C086711:cysteine-rich fibroblast growth factor receptor; D005643:Fucose; D005647:Fucosyltransferases