Elevated T Cell Receptor Signaling Identifies a Thymic Precursor to the TCRαβ(+)CD4(-)CD8β(-) Intraepithelial Lymphocyte Lineage

McDonald BD, Bunker JJ, Ishizuka IE, Jabri B, Bendelac A.

Immunity. 2014 Aug 21;41(2):219-29. doi: 10.1016/j.immuni.2014.07.008. Epub 2014 Aug 14.

From left to right: Isabel Ishizuka, Benjamin McDonald, and Jeffrey Bunker

From left to right: Isabel Ishizuka, Benjamin McDonald, and Jeffrey Bunker

The developmental pathway that TCRαβ+CD8αα+ intestinal intraepithelial lymphocytes (here called unconventional iIEL) follow has long remained a mystery. In their recent paper, McDonald et al. cloned and forced the expression of TCRs isolated from unconventional iIEL and came to the following conclusions. First, TCR specificity drives commitment to the unconventional iIEL lineage. Second, iIEL TCRs induce a pattern of thymic negative selection, with most cells expressing these TCR undergoing apoptosis but a small proportion of them escaping deletion and selectively maturing into unconventional iIEL. Third, the post-selection precursors to unconventional iIEL are the CD4loCD8lo(DPlo)CD69hiPD-1hi thymocytes, a population that largely overlaps with the general pool of MHC class I- or MHC class II-autoreactive thymocytes that undergo negative selection. By downregulating the expression of both CD4 and CD8b coreceptors, these cells largely lose their ability to recognize self ligands and, instead proceed to express natural killer lineage receptors with innate immune recognition properties. Altogether, the results establish that most unconventional iIEL originate from autoreactive thymocytes that barely escape thymic clonal deletion by downregulating co-receptors, and are subsequently recycled into long-lived innate-like cytolytic effectors homing to the intestinal epithelium. PubMed:25131532