LOSS OF TH1-ASSOCIATED FUNCTION IN PERIPHERAL T-CELLS BUT NOT THYMOCYTES IN TOLERANCE TO MAJOR HISTOCOMPATABILITY COMPLEX ALLOANTIGEN

Mice of the strains A.TH and A.TL were rendered neonatally tolerant to class II major histocompatibility complex (MHC) by the injection of ( A.TH x A.TL)F1 spleen and bone marrow cells within 24 hr of birth. Spl een and thymus cells from adult tolerant mice bearing long-term surviv ing skin grafts were compared with those from normal mice for their in vitro reactivity towards the tolerogen. In a primary mixed lymphocyte reaction (MLR), spleen cells from normal mice proliferated in respons e to 'tolerogen', generated cytotoxic cells and produced interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) but no IL-4 or IL-5. In contr ast, although spleen cells from tolerant mice proliferated and produce d IL-2, they failed to generate cytotoxic cells or produce IFN-gamma b ut produced large amounts of IL-4 and IL-5. The loss of the ability of tolerant cells to generate cytotoxicity or IFN-gamma was profound in that no activity was detected in a secondary MLR and mRNA for IFN-gamm a could not be detected by reverse transcription polymerase chain reac tion (RT-PCR). To see whether the alteration in function occurred cent rally or peripherally, thymus cells from normal and tolerant mice were tested for function. Normal thymocytes produced IFN-gamma, IL-4 and I L-5 in a primary MLR and generated cytotoxic cells in a secondary MLR. In contrast to spleen cells, thymus cells from tolerant mice retained their ability to generate IFN-gamma or cytotoxic cells in response to tolerogen. Overall the results point to a profound switch in peripher al tolerogen-specific responses from a Th1-biased response in normal m ice to a Th2-biased response in tolerant mice and suggest that the alt eration in function is post thymic.