We are very proud to share our last contribution to our quest to identify the cause of immunodeficiencies. Our participation to this collaborative work has revealed that even if CARMIL2 was described to be involved in CD28-mediated signaling during T cell activation, CARMIL2 deficiency underlies a broader clinical phenotype than CD28 deficiency (that we had also participated to describe: Béziat et al., Cell 2022).
Strikingly, CARMIL2 deficient patients had been previously described but the effect of the mutation were never validated. Why? Researchers were studying the impact of the mutations on the isoform described in databases, but we now show that this isoform is not functional. Instead, we describe a new isoform, predominant in T cells, and that exert the CARMIL2 functions in these cells. We tested mutated alleles from 89 patients and 52 families and shown that they impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28, as well as its broader involvement in T cell activation.
Read the full story here: https://rupress.org/jem/article/220/2/e20220275/213746/Human-CARMIL2-deficiency-underlies-a-broader
Source: Lévy et al., J Exp Med, 2023