Oral Presentation Australasian Society for Immunology Annual Scientific Meeting 2014

The transcriptional regulator Blimp1 and its homologue Hobit cooperatively regulate tissue-residency of lymphocytes (#8)

Klass PJM van Gisbergen 1 2 , Laura K Mackay 3 , Natasja AM Kragten 1 , Simon Preston 4 , Cyril Seillet 2 , Asolina Braun 3 , Daniel G Pellici 3 , Dale I Godfrey 3 , Gabrielle T Belz 2 , Marc Pellegrini 5 , Thomas Gebhardt 3 , Renee AW van Lier 1 , Frank R Carbone 3 , Axel Kallies 2
  1. Dept. of Hematopoiesis, Sanquin Research, Amsterdam, 1066 CX, Netherlands
  2. Division of Molecular Immunology, Walter and Eliza Hall Institute, Parkville, VIC 3052, Australia
  3. Dept. of Microbiology and Immunology, University of Melbourne, Parkville, VIC 3010, Australia
  4. Division of Infection and Immunity, Walter and Eliza Hall Institute, Parkville, VIC 3052, Australia
  5. Division of Infection and Immunity, Walter and Eliza Hall Institute, Parkville, VIC 3052, Australia

Tissue-resident memory T-cells (Trm) constitute a non-circulating subset of memory cells that localize to sites of pathogen entry where they provide immediate protection against reinfection. Trm form a unique population of T-cells distinct from other memory T-cell subsets, including central and effector memory T cells. In contrast to circulating memory T-cells, Trm express CD69 which promotes tissue retention and silence the expression of CCR7 and S1P1 allowing them to permanently remain at peripheral tissue sites.

The transcriptional regulation of Trm differentiation is only incompletely understood a transcription factor specific to Trm has not been established to date. The transcriptional regulator Blimp1 is known to promote differentiation of short-lived effector cells. Using reporter systems and transcriptional profiling, we have found that Blimp1 is also expressed in Trm. Intriguingly, the transcription factor Hobit, a Blimp1 homologue not expressed in effector T-cells, was specifically up-regulated in Trm. We therefore examined Trm development after viral infection of mice lacking Blimp1 or Hobit, or mice with a combined deficiency in both factors. Neither Blimp1 nor Hobit, alone or in combination, were required the formation of effector T-cells within the skin or the development of conventional memory cells. In contrast, combined deficiency in Blimp1 and Hobit resulted in the loss of skin-resident Trm. Further analysis revealed that Blimp1 and Hobit suppressed expression of KLF2, CCR7 and S1P1, suggesting that these factors directly regulated tissue retention of Trm.

Similar to skin-resident memory T-cells, Trm developing after infection with LCMV, and other tissue-resident lymphocytes including Trm-like populations of gut and liver, NKT-cells and ILC1 expressed Hobit and Blimp1. Maintenance of these cells at peripheral sites required the combined activity of both factors. Thus, while Blimp1 is a critical determinant of multiple stages of effector T-cell development, Hobit is specifically upregulated in lymphocytes that enter non-lymphoid tissues where it collaborates with Blimp1 in the establishment of a transcriptional profile that supports tissue residency.