Hobit and Blimp‐1 instruct the differentiation of iNKT cells into resident‐phenotype lymphocytes after lineage commitment

• Published in: European journal of immunology Vol. 52; no. 3; pp. 389 - 403
• Main Authors: Kragten, Natasja AM, Taggenbrock, Renske LRE, Parga Vidal, Loreto, van Lier, Rene AW, Stark, Regina, van Gisbergen, Klaas PJM
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01-03-2022; John Wiley and Sons Inc
• Subjects: Animals; Autoimmune diseases; Basic; Blimp‐1; CD1d antigen; CD69 antigen; Cell Differentiation; Differentiation; Gene Expression Regulation; Genotype & phenotype; Hobit; Immunological memory; Inflammation; iNKT cells; Innate immunity; L-selectin; Lineage commitment; Lymphocytes T; Memory cells; Mice; Mice, Inbred C57BL; Natural Killer T-Cells; Phenotype; Phenotypes; Thymus; Tissue residency; Transcription Factors - metabolism; Lineage commitment; Tissue residency; Differentiation; Hobit; iNKT cells; Blimp-1
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.202149360

iNKT cells are CD1d‐restricted T cells that play a pro‐inflammatory or regulatory role in infectious and autoimmune diseases. Thymic precursors of iNKT cells eventually develop into distinct iNKT1, iNKT2, and iNKT17 lineages in the periphery. It remains unclear whether iNKT cells retain developmental potential after lineage commitment. iNKT cells acquire a similar phenotype as tissue‐resident memory T cells, suggesting that they also differentiate along a trajectory that enables them to persist in peripheral tissues. Here, we addressed whether lineage commitment and memory differentiation are parallel or sequential developmental programs of iNKT cells. We defined three subsets of peripheral iNKT cells using CD62L and CD69 expression that separate central, effector, and resident memory phenotype cells. The majority of iNKT1 cells displayed a resident phenotype in contrast to iNKT2 and iNKT17 cells. The transcription factor Hobit, which is upregulated in iNKT cells, plays an essential role in their development together with its homolog Blimp‐1. Hobit and Blimp‐1 instructed the differentiation of central memory iNKT cells into resident memory iNKT cells, but did not impact commitment into iNKT1, iNKT2, or iNKT17 lineages. Thus, we conclude that memory differentiation and the establishment of residency occur after lineage commitment through a Hobit and Blimp‐1‐driven transcriptional program.
iNKT cells differentiate into separate iNKT1, iNKT2, and iNKT17 lineages and acquire a resident memory phenotype. We found that lineage commitment preceded the acquisition of residency‐associated molecules in iNKT cells. The transcription factors Hobit and Blimp‐1 instructed the acquisition of a resident memory phenotype in iNKT cells.