IL-2 and IL-4 double knockout mice reject islet allografts: a role for novel T cell growth factors in allograft rejection.
T cell growth factors (TCGFs) play a critical role in allograft rejection by promoting the activation and proliferation of alloreactive T cells. To determine whether IL-2 and IL-4 are of quintessential importance in allograft rejection and to identify possible alternative TCGFs, we have bred IL-2(-/-) and IL-4(-/-) double knockout (DKO) mice and studied islet allograft rejection using the DKO mice as allograft recipients. Although mononuclear leukocytes from DKO mice did not mount a proliferative response in vitro in response to anti-CD3 stimulation, crude islet allografts were vigorously rejected by DKO mice (mean survival time 17 +/- 7, n = 8) as compared with wild-type controls (mean survival time 13 +/- 4, n = 7). Treatment of DKO mice with anti-CD3 or rapamycin markedly prolonged the islet allograft survival. An analysis of intragraft cytokine gene transcripts showed robust expression of IL-7 and IL-15. In contrast, intragraft IL-9 gene transcripts were not detected in either wild-type or DKO mice. Provision of exogenous IL-2, IL-4, IL-7, or IL-15, but not IL-9, supports the proliferation of anti-CD3 activated DKO splenic leukocytes in vitro. Blocking the common gamma c of IL-2 receptor, a shared essential signaling component by receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, prolonged the survival of islet allografts in DKO mice. Hence, a T cell dependent allograft rejection enabled by rapamycin-sensitive signals or signals mediated by binding of the gamma c chain occurs in the absence of both IL-2 and IL-4. Non-T cell-derived TCGFs, especially IL-7 and IL-15, may play an active role in supporting allograft rejection.
Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
X C
XC
Li
P
P
Roy-Chaudhury
W W
WW
Hancock
R
R
Manfro
M S
MS
Zand
Y
Y
Li
X X
XX
Zheng
P W
PW
Nickerson
J
J
Steiger
T R
TR
Malek
T B
TB
Strom
D000818:Animals; D003601:Cytotoxicity Tests, Immunologic; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D007376:Interleukin-2 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D015847:Interleukin-4 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014158:Transcription, Genetic / Q000276:immunology; D014184:Transplantation, Homologous
D007376:Interleukin-2; D015847:Interleukin-4