Loss of Th1-associated function in peripheral T cells but not thymocytes in tolerance to major histocompatibility 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. Spleen and thymus cells from adult tolerant mice bearing long-term surviving 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 response to 'tolerogen', generated cytotoxic cells and produced interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) but no IL-4 or IL-5. In contrast, although spleen cells from tolerant mice proliferated and produced IL-2, they failed to generate cytotoxic cells or produce IFN-gamma but 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-gamma could not be detected by reverse transcription polymerase chain reaction (RT-PCR). To see whether the alteration in function occurred centrally or peripherally, thymus cells from normal and tolerant mice were tested for function. Normal thymocytes produced IFN-gamma, IL-4 and IL-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 peripheral tolerogen-specific responses from a Th 1-biased response in normal mice to a Th2-biased response in tolerant mice and suggest that the alteration in function is post thymic.