Role of CXCR3-induced donor T-cell migration in acute GVHD.
OBJECTIVE
The chemokine receptor CXCR3 has an important role in the migration of effector T cells. To investigate the role of CXCR3 on donor cells in acute graft vs host disease (GVHD) we used a well-defined experimental bone marrow transplantation (BMT) model where acute GVHD is mediated by donor CD8(+) T cells against minor histocompatibility antigens. METHODS; Lethally irradiated C3H.SW recipients were transplanted from either wild-type B6 or CXCR3(-/-) B6 donors. Donor T-cell expansion was analyzed in the spleen and small intestine of recipients by FACS. Donor T-cell function was analyzed by cytokine secretion. The severity of acute GVHD was assessed by histopathological analysis of intestine and liver, GVHD clinical scores, and survival after BMT.


RESULTS
Significantly higher numbers of donor CD8(+) CXCR3(-/-) T cells were found in the spleen on days +7 and +14 compared to donor wild-type T cells. By contrast, the number of CD8(+) T cells in the small bowel of BMT recipients from CXCR3(-/-) donors was sevenfold lower than from wild-type donors. Systemic concentrations of INF-gamma and TNF-alpha were equivalent between groups. Animals that received CXCR3(-/-) donor T cells demonstrated diminished GI tract and liver damage and showed improved survival after BMT compared to recipients of wild-type donor cells (43% vs 0%, p<0.001).


CONCLUSIONS
The migration of donor CD8(+) T cells to GVHD target organs such as the intestine depends on the expression of CXCR3 and contributes significantly to GVHD damage and overall mortality.
Duffner
Ulrich
U
Departments of Internal Medicine and Pediatrics, University of Michigan Cancer Center, Ann Arbor, Michigan 48109-0942, USA.
Lu
Bao
B
Hildebrandt
Gerhard C
GC
Teshima
Takanori
T
Williams
Debra L
DL
Reddy
Pavan
P
Ordemann
Rainer
R
Clouthier
Shawn G
SG
Lowler
Kathy
K
Liu
Chen
C
Gerard
Craig
C
Cooke
Kenneth R
KR
Ferrara
James L M
JL
D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D002465:Cell Movement; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology* / Q000401:mortality; D007371:Interferon-gamma / Q000032:analysis; D008099:Liver / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000502:physiology*; D014019:Tissue Donors; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma