Recombination activation gene-2-deficient blastocyst complementation analysis reveals an essential role for nuclear factor I-A transcription factor in T-cell activation

摘要

Nuclear factor I (NFI)-A is a member of the NFI family of transcription factors implicated in regulation of granulocyte differentiation. However, its role in the lymphoid lineage is not known. NFI-A deficiency results in perinatal lethality, thus precluding analysis of the role of NFI-A in lymphocyte development and function. Using recombination activation gene-2-deficient (RAG-2^−/−) blastocysts and embryonic stem cells with homozygous NFI-A gene deletion, we show an essential role for NFI-A in T-cell activation. NFI-A^−/−→RAG-2^−/− chimeric mice had normal distributions of CD4⁻CD8⁻ double negative, CD4⁺CD8⁺ double positive, CD4⁺CD8⁻ and CD4⁻CD8⁺-single positive cells in the thymus and CD4⁺CD8⁻ and CD4⁻CD8⁺ cells in spleen and lymph nodes. However, NFI-A^−/−→RAG-2^−/− mice had severely reduced thymus size and hypocellularity. The decrease in thymocytes and peripheral T cells in NFI-A^−/−→RAG-2^−/− chimeric mice is attributed to proliferative defects associated with decreased blast transformation, CD69 expression and DNA synthesis in response to T antigen receptor stimulation. Interestingly, NFI-A-null T cells showed increased levels of c-myc transcription that is inhibited in response to antigen receptor-mediated activation. These studies demonstrate for the first time a requirement for the NFI-A transcription factor in antigen receptor-induced T-cell activation events.