ALLOANTIGEN PRIMING AFTER TOTAL LYMPHOID IRRADIATION ALTERS ALLOIMMUNE CYTOKINE RESPONSES

Total lymphoid irradiation (TLI) treatment represents a model of acqui red tolerance, as TLI-treated mice develop donor-specific tolerance wh en exposed to alloantigens shortly after completing TLI, To determine whether immunoredirection plays a role in immunologic tolerance in TLI , we examined whether antigen priming in the immediate post-TLI stage altered the cytokine profile toward Th2. Compared with splenocytes iso lated from control primed mice, the splenocytes from TLI-primed mice f ailed to proliferate to immunogen in mixed leukocyte reaction cultures but proliferated normally to third-party alloantigen. Whole spleen an d purified CD4 cells isolated from TLI-primed mice produced more inter leukin (IL)-4 and less gamma-interferon (IFN-gamma) in response to imm unogen-bearing stimulator cells than controls, resulting in higher IL- 4 to IFN-gamma ratios. The CD4 subset from TLI-primed mice contained m ore IL-4-producing and fewer IFN-gamma-producing cells, suggesting tha t priming after TLI shifted CD4 maturation toward Th2 cells. Surprisin gly, TLI-primed mice contained no immunogen-responsive, IFN-gamma-prod ucing CD8 cells, indicating that priming after TLI abrogated developme nt of this CD8 subset. In summary, the data show that priming in the i mmediate post-TLI phase shifts the allospecific memory cytokine patter n toward Th2 cytokines by enhancing IL-4-producing CD4 cells and preve nting maturation of IFN-gamma-producing CD8 cells. We speculate that t he cytokine milieu at the time of antigen priming drives differentiati on of the tolerogen-specific immune response toward Th2 cells, because splenocytes isolated immediately after TLI produced high levels of IL -4 and little IL-2. The enhanced Th2 pattern that developed in the TLI -primed mice suggests that immunoredirection may also occur in the TLI model of tolerance.