Impaired Tissue Homing by the Ikzf3 Variant is Mediated by Interfering with Ikaros Function

AIOLOS, encoded by , is a member of the IKZF family of proteins that plays an important role in regulating late B-cell differentiation. Human individuals heterozygous for the AIOLOS p.N160S variant displayed impaired humoral immune responses as well as impaired B and T cell development. We have previously reported that a mouse strain harboring an allele that corresponds to human recapitulated immune-deficient phenotypes, such as impaired B cell development and loss of CD23 expression. In this study, we investigated the effect of the variant and found that B1a cell development was impaired in mice. In addition, CD62L expression was severely decreased in both B and T lymphocytes by the mutation, in a dose-dependent manner. Mixed bone marrow chimera experiments have revealed that most immunodeficient phenotypes, including low CD62L expression, occur in intrinsic cells. Interestingly, while lymphocytes were still present in the spleen, they were completely outcompeted by control cells in the lymph nodes, suggesting that the capacity for homing or retention in the lymph nodes was lost due to the mutation. The homing assay confirmed severely decreased homing abilities to lymph nodes of B and T lymphocytes but selective enrichment of CD62L expressing lymphocytes in lymph nodes. This finding suggests that impaired CD62L expression is the major reason for the impaired homing capacity caused by the mutation. Interestingly, an excess amount of Ikaros, but not Aiolos, restored CD62L expression in B cells. Together with the loss of CD62L expression due to Ikaros deficiency, the Aiolos mutant protein likely interferes with Ikaros function through heterodimerization, at least in activating the gene encoding CD62L expression. Thus, our results revealed that Aiolos causes some immunodeficient phenotypes the pathogenesis referred to as the heterodimeric interference as observed for Aiolos variant.