One proposed reason for intestinal inflammation in Crohn’s disease (CD) is a pathologic antigen-driven immune response. However, the precise combination of the immune receptors involved in the pathogenesis and their antigenic specificities remains unknown.
Recently, we described a subset of CD-associated invariant T (CAIT) cells, which we determined as enriched in the peripheral blood of CD patients, and present in intestinal samples. The unique features of these cells include an invariant TCRα chain resulting from the recombination of TRAV12-1 and TRAJ6 gene segments, permissive pairing with various TCRβ chains, and an innate-like, yet heterogeneous, phenotype.
Remarkably, earlier studies revealed similar T cell clones (PMID: 34417291, 15342907). These clones recognize a small molecule antigen, phenyl pentamethyldihydrobenzofuransulfonate (PPBF), in a CD1d-restricted manner. We cloned CAIT TCRs and expressed them in a Jurkat NFAT-GFP reporter cell line. In vitro assays confirmed the specificity to PPBF and CD1d restriction of CAIT TCRs.
Besides PPBF, we tested a set of other sulfur-containing molecules, such as derivatives of the cholic acid and drugs 6-mercaptopurine, azathioprine, and sulfasalazine. We also tested biles from patients with primary sclerosing cholangitis + CD and lysates from various pathogenic and symbiotic microbes including Clostridium difficile, Escherichia coli, Debaryomyces hansenii, Lactobacillus rhamnosus, and Mycobacteria species. None of the agents induced an antigen-specific activation.
In conclusion, CAIT cells seem to represent a previously understudied subset of unconventional T cells. They are present in healthy population and enriched in individuals with Crohn’s disease. Our current research aims to further profile other PPBF-CD1d-restricted T cells from Crohn’s disease patients with the goal of characterizing all cells exhibiting the shared specificity in the context of this disease. In addition, we are in the process of validating the CAIT-CD association in an independent, treatment-naive CD sample. We will present the state-of-the-art of our research at the conference.