Knockout CD73 reduces thymus-derived lymphocytes and clinical phenotype of Foxp3 +Treg deficient autoimmune scurfy mice

Abstract

Abstract CD73 is ubiquitously expressed and regulates critical functions across multiple organ systems. The combination of CD39 and CD73 degrade ATP to adenosine that shifts ATP-driven pro-inflammatory immune cell activity toward an anti-inflammatory state. This immunological switch is a major mechanism for Tregs to control inflammation. In the Foxp3 +Treg deficient scurfy (SF) mouse, a mouse model of human IPEX syndrome, we showed that a specific probiotic exhibits therapeutic effects via probiotic-derived adenosine. We generated CD73KOSF mice by removing host CD73, aiming to identify a specific probiotic-CD73 effect. CD73KOSF mice were generated by breeding heterozygous-Foxp3sf/J females to CD73KO male mice with genotyping confirmation. We unexpectedly observed that KO of CD73 in SF mice reduced clinical severity. CD73KOSF mice showed reduced ear thickness, increased ear size, improved deformed ears, and reduced scurfy skin compared to SF mice. SF mice had increased CD4 +and CD8 +T cells compared to WT mice; KO of CD73 in SF mice significantly reduced the numbers of these cells in the spleen and blood to normal. However, the inflammatory cytokines and chemokines in plasma and lymphocyte infiltration in the liver of CD73KOSF were similar to those in SF mice. We further identified that KO of CD73 in SF mice reduced the numbers of CD3 +T and DP CD4 +CD8 +T cells in the thymus compared to those in SF mice, indicating that reducing clinical phenotype specifically scurfy tails and deformed ears may mainly be due to reduced central and peripheral lymphoproliferation. This study provides data to aid further discovery of CD73 as a target to improve dermatitis-one of the most common symptoms in Treg-deficiency-associated primary immune deficiencies. Supported by grants from NIH/NIAID (R03AI153725)