Transcription factors define tissue T cells The immune system fights microbial invaders by maintaining multiple lines of defense. For instance, specialized memory T cells [resident memory T cells (Trms)] colonize portals of pathogen entry, such as the skin, lung, and gut, to quickly halt reinfections. Mackay et al. now report that in mice, Trms as well as other tissue-dwelling lymphocyte populations such as natural killer cells share a common transcriptional program driven by the related transcription factors Hobit and Blimp1. Tissue residency and retention of lymphocytes require expression of Hobit and Blimp1, which, among other functions, suppress genes that promote tissue exit. Science, this issue p. 459 Tissue-dwelling lymphocyte populations share a common transcriptional signature. Tissue-resident memory T (Trm) cells permanently localize to portals of pathogen entry, where they provide immediate protection against reinfection. To enforce tissue retention, Trm cells up-regulate CD69 and down-regulate molecules associated with tissue egress; however, a Trm-specific transcriptional regulator has not been identified. Here, we show that the transcription factor Hobit is specifically up-regulated in Trm cells and, together with related Blimp1, mediates the development of Trm cells in skin, gut, liver, and kidney in mice. The Hobit-Blimp1 transcriptional module is also required for other populations of tissue-resident lymphocytes, including natural killer T (NKT) cells and liver-resident NK cells, all of which share a common transcriptional program. Our results identify Hobit and Blimp1 as central regulators of this universal program that instructs tissue retention in diverse tissue-resident lymphocyte populations.

Hobit and Blimp1 instruct a universal transcriptional program of tissue-residency in lymphocytes

Bcl6 and Prdm1 (Blimp1) are a pair of transcriptional factors that repressing each other in mammals Prdm1 represses the expression of bcl6 by binding a cis-element of the bcl6 gene in mammals The homologs of Bcl6 and Prdm1 have been identified in teleost fish However, whether these two factors regulate each other in the same way in fish like that in mammals is not clear In this study, the regulation of bcl6aa by Prdm1 was investigated in medaka The mRNA of bcl6aa has three variants (bcl6aaX1-X3) at the 5'-end by alternative splicing detected by RT-PCR The three variants can be detected in adult tissues and developing embryos of medaka Prdm1a and prdm1b are expressed in the tissues and embryos where and when bcl6aa is expressed The expression of prdm1a was high while the expression of bcl6aa was low, and vice versa, detected in the spleen after stimulation with LPS or polyI:C In vitro reporter assay indicated that bcl6aa could be directly repressed by both Prdm1a and Prdm1b in a dosage-dependent manner After mutation of the key base, G, of all predicted binding sites in the core promoter region of bcl6aa, the repression by Prdm1a and/or Prdm1b disappeared The binding site of Prdm1 in the bcl6aa gene is GAAAA(T/G) These results indicate that both Prdm1a and Prdm1b directly repress the expression of bcl6aa by binding their binding sites where the 5'-G is critical in medaka fish

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Shi Duan

Papers

Alternative splicing of medaka bcl6aa and its repression by Prdm1a and Prdm1b

Mep50 is essential for embryonic development in medaka fish.