Biallelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterized by severe pathogen infections, eczema, allergies, malignancy, and impaired humoral responses. These clinical features result from functional defects in most lymphocyte lineages. Thus, DOCK8 plays a key role in immune cell function. Hematopoietic stem cell transplant (HSCT) is curative for DOCK8 deficiency. While previous reports have described clinical outcomes for DOCK8 deficiency following HSCT, the effect on lymphocyte reconstitution and function has not been investigated. Our study determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of αβ T and MAIT cells were reduced, while γδT cells were increased in DOCK8-deficient patients. HSCT improved abnormal lymphocyte function in DOCK8-deficient patients. Elevated total and allergen-specific IgE in DOCK8-deficient patients decreased over time following HSCT. Our results document the extensive catalog of cellular defects in DOCK8-deficient patients and the efficacy of HSCT in correcting these defects, concurrent with improvements in clinical phenotypes. Overall, our findings reveal mechanisms at a functional cellular level for improvements in clinical features of DOCK8 deficiency after HSCT, identify biomarkers that correlate with improved clinical outcomes, and inform the general dynamics of immune reconstitution in patients with monogenic immune disorders following HSCT.
Bethany A. Pillay, Danielle T. Avery, Joanne M. Smart, Theresa Cole, Sharon Choo, Damien Chan, Paul E. Gray, Katie Frith, Richard Mitchell, Tri Giang Phan, Melanie Wong, Dianne E. Campbell, Peter Hsu, John B. Ziegler, Jane Peake, Frank Alvaro, Capucine Picard, Jacinta Bustamante, Benedicte Neven, Andrew J. Cant, Gulbu Uzel, Peter D. Arkwright, Jean-Laurent Casanova, Helen C. Su, Alexandra F. Freeman, Nirali Shah, Dennis D. Hickstein, Stuart G. Tangye, Cindy S. Ma