Alloantigen priming after total lymphoid irradiation alters alloimmune cytokine responses.

Total lymphoid irradiation (TLI) treatment represents a model of acquired tolerance, as TLI-treated mice develop donor-specific tolerance when 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 isolated from control primed mice, the splenocytes from TLI-primed mice failed to proliferate to immunogen in mixed leukocyte reaction cultures but proliferated normally to third-party alloantigen. Whole spleen and purified CD4 cells isolated from TLI-primed mice produced more interleukin (IL)-4 and less gamma-interferon (IFN-gamma) in response to immunogen-bearing stimulator cells than controls, resulting in higher IL-4 to IFN-gamma ratios. The CD4 subset from TLI-primed mice contained more IL-4-producing and fewer IFN-gamma-producing cells, suggesting that priming after TLI shifted CD4 maturation toward Th2 cells. Surprisingly, TLI-primed mice contained no immunogen-responsive, IFN-gamma-producing CD8 cells, indicating that priming after TLI abrogated development of this CD8 subset. In summary, the data show that priming in the immediate post-TLI phase shifts the allospecific memory cytokine pattern toward Th2 cytokines by enhancing IL-4-producing CD4 cells and preventing maturation of IFN-gamma-producing CD8 cells. We speculate that the cytokine milieu at the time of antigen priming drives differentiation 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.