Interferon-gamma (IFN-gamma) is a potent regulator of immunological response including B cell development. To examine the role of IFN-gamma on B cell development, a construct in whichthe murine IFN-gamma gene was placed under the control of the murine Ig-lambda gene enhancer was used to generate IFN-gamma transgenic mice. Analysis of mice transgenic for the IFN-gamma gene revealed elevated numbers of IFN-gamma expressing cells in both the bone marrow and spleen. While in normal littermates, steady state levels of IFN-gamma transcripts (in bone marrow cells) and protein (in bone marrow cells and serum) are virtuallyundetectable, IFN-gamma transgenic mice showed dramatically increased amounts of both. Additionally, IFN-gamma transgenic mice showed a pronounced reduction in B-lineage cells inthe bone marrow, spleen and lymph nodes. Overall, a 5-10 fold reduction in the number of B220(+) cells were observed in the bone marrows of IFN-gamma mice when compared to normallittermates. Characterization of B cells present in the bone marrow by immunophenotype revealed that all of the B220(+) was CD43 (+). Examination (by RT-PCR) of total RNA prepared from bone marrow cells isolated from IFN-gamma transgenic mice revealed no detectable amounts of steady state transcripts for genes specific for early stages of B cell development (e.g., VpreB, lambda-5, Ig-alpha, Rag-1 and Rag-2). However, steady state transcripts of the TdT gene were detected. These data indicate that in IFN-gamma transgenic mice B cell development is arrested very early, at the preProB to ProB -cell stage (fraction A to B cells) similar to the developmental arrest seen in Rag-1/-2 knockout mice. Treatment of IFN-gamma transgenic mice with injections of anti-IFN-gamma antibody, anti-IFN-gamma receptor antibody, or cyclosporin A alone or in combination, did not reverse the block to B cell development. Transfer of B cells from IFN-gamma transgenic miceinto normal hosts also failedto rescue the IFN-gamma transgene positive B cells, suggesting that the factor responsible forthe developmental block was intrinsic to the B cell and not solely environmental. Crossing the IFN-gamma transgenic mice with either bcl-2 transgenic mice or anti-phosphocholine specific immunoglobulin heavy/light chain transgenic mice also failed to rescue B cell development inthese mice. The absence of detectable transcripts for genes expressed early in B cell development, including Rag-1/-2, coupled with the inability of functionally rearranged anti- phosphocholine IgH/L chains to rescue B cell development in IFN-gamma transgenic mice suggests a role for IFN-gamma in regulating transcriptional events during commitment to andprogression through the very early stages of B cell development. Perhaps the developmental arrest affected by IFN-gamma expression is related to its ability to antagonize IL-7 induced proliferation of progenitor B cells. Examination and identification of the transcriptional events regulated by IFN-gamma expression during early B cell development will provide valuable insight into genes which are essential for commitment of cells to the B cell lineage and subsequent progression through the early stages of B cell development. - gamma interferon transgenic mouse; transgenic B cell arrest; B cell development; Pro-B cells;
