THE INFLUENCE OF ALLO-CLASS-II MHC-SPECIFIC TH2 CELLS ON THE GENERATION OF CD4 AND CD8 CYTOTOXIC T-CELLS TO ASSOCIATED CLASS-I AND CLASS-IIMHC ALLOANTIGEN

There is considerable interest in whether CD4 T cell function can affe ct the outcome of allogeneic transplants. In mice tolerant to an isola ted class II MHC disparity, the normal Th1 activity in vitro associate d with graft rejection is switched to Th2 in tolerant animals. Because clinical transplants involve multiple class I and II MHC disparities we tested how the switch to Th2 activity of tolerant mice would affect the generation of CD4 and CD8 cytotoxic T cells (CTL) against MHC all oantigens to which the mice were not tolerant. A.TH mice ((KIDd)-I-k-D -s) were rendered neonatally tolerant of A.TL ((KIDd)-I-k-D-k) and the generation of CD4 or CD8 CTL measured in a mixed lymphocyte reaction (MLR) against (A.TLxB6)F-1 stimulators. Normal mice generated CD4 CTL against both A.TL and B6 ((KIDb)-I-b-D-b), but tolerant mice were unab le to generate cytotoxicity against either A.TL or B6. However, tolera nt cells were able to generate CD8 CTL against B6. IL-4 inhibited the generation of CD4, but not CD8, CTL by normal cells and anti-IL-4 anti body was shown to increase the generation of CD4 CTL against B6 in F-1 stimulated cultures. Overall the results showed that a Th2 response c ould inhibit the generation of CD4 CTL against concomitant alloantigen in a process at least partially involving IL-4, but that, conversely, tolerant Th2 cells could help in the generation of CD8 CTL. The resul ts suggest that with whole MHC disparities a simple change of CD4 T ce lls to Th2 would not be enough to procure graft acceptance.