Evidence for functional heterogeneity of rat CD4+ T cells in vivo. Differential expression of IL-2 and IL-4 mRNA in recipients of cardiac allografts.
The in vivo relevance of functional dichotomy of CD4+ Th clones was studied by analyzing the induction of mRNA encoding for Th1- (IL-2) and Th2- (IL-4) specific lymphokines in a model of accelerated (24 h) cardiac allograft (Tx) rejection in presensitized rats. The polymerase chain reaction-assisted screening of total cellular RNA from cardiac Tx of otherwise untreated sensitized recipients has revealed sequential lymphokine mRNA expression, with the peak of IL-2 mRNA (6-12 h) preceding that for IL-4 mRNA, which was maximal at the time of actual Tx loss (24 h). Both IL-2 and IL-4 transcripts could be readily detected by polymerase chain reaction analysis in the spleens during the course of accelerated rejection. Treatment of prospective cardiac Tx recipients with BWH-4, a mouse anti-rat CD4 mAb, abrogated rejection at 24 h and prolonged cardiac Tx survival to ca. 11 days, coinciding with significantly diminished IL-2 mRNA expression. In contrast, CD4 targeted therapy preserved intra-Tx and splenic transcription of the IL-4 gene. Spleen lymphocytes from mAb-conditioned recipients separated by magnetic microspheres into phenotypically distinct subpopulations, showed differential induction of IL-2 and IL-4 mRNA. Thus, IL-2 mRNA was at most very weakly expressed, whereas IL-4 transcription was strongly induced both in CD4+ T cells and its OX-22- subset. This study demonstrates the induction of IL-4 mRNA in situ in the rat system, describes discordant elaboration of IL-2 and IL-4 mRNA in untreated/anti-CD4 mAb-treated cardiac Tx recipients, and identifies OX-22- CD4+ T cells as the IL-4 mRNA producers. Thus, these results provide evidence for functional heterogeneity of rat CD4+ T cells in vivo, as defined by divergent mRNA lymphokine transcription profiles.
Harvard Medical School, Department of Medicine, Beth Israel Hospital, Boston, MA 02115.
I
I
Papp
K J
KJ
Wieder
T
T
Sablinski
P J
PJ
O'Connell
E L
EL
Milford
T B
TB
Strom
J W
JW
Kupiec-Weglinski
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015704:CD4 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D006084:Graft Rejection; D016027:Heart Transplantation / Q000276:immunology*; D007376:Interleukin-2 / Q000235:genetics*; D015847:Interleukin-4 / Q000235:genetics*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D011919:Rats, Inbred Strains; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D007376:Interleukin-2; D012333:RNA, Messenger; D015847:Interleukin-4