Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients
Bethany A. Pillay, … , Stuart G. Tangye, Cindy S. Ma
Bethany A. Pillay, … , Stuart G. Tangye, Cindy S. Ma
Published April 25, 2019
Citation Information: JCI Insight. 2019;4(11):e127527. https://doi.org/10.1172/jci.insight.127527.
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Research Article Immunology Infectious disease

Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients

Abstract

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.

Authors

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

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Figure 1

DOCK8 is highly expressed in lymphocyte subsets, absent in DOCK8-deficient patients and restored following HSCT.

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DOCK8 is highly expressed in lymphocyte subsets, absent in DOCK8-deficie...
(A) PBMCs from healthy donors (n = 3) were stained with Abs against CD3, CD4, CD8, CD20, CD56, CD161, and TCR Vα24, Vβ11, and Vα7.2. The cells were then fixed, permeabilized, and stained with anti-DOCK8 mAb. Expression of intracellular DOCK8 in total T cells (CD3+), CD4+ T cells (CD3+CD4+CD8–), CD8+ T cells (CD3+CD4–CD8+), B cells (CD20+CD3–), NK cells (CD3–CD56+), NKT cells (CD3+TCRVα24+Vβ11+), and MAIT cells (CD3+CD161+TCRVα7.2+) was then determined. Data represent the average geometric MFI ± SEM of different lymphocyte subsets from 3 unrelated donors labeled with anti-DOCK8 mAb less the MFI of cells labeled with isotype control mAb. (B and C) PBMCs from healthy donors (n = 20) or DOCK8-deficient patients before (n = 4) or following HSCT (pHSCT; n = 15–16) were stained with Abs against CD4, CD8, and CD20 before fixing, permeabilization, and staining for DOCK8. DOCK8 expression was determined in total lymphocytes (B), as well as in CD4+ T cells, CD8+ T cells, and CD20+ B cells (C). The histogram in B depicts DOCK8 expression in total lymphocytes from 1 representative healthy donor, and lymphocytes from the same DOCK8-deficient patient before and after transplant as well as an isotype control. The graph in C represents the mean MFI ± SEM of DOCK8 expression (minus MFI of isotype control mAb). Statistical analysis was performed using unpaired t test with Welch’s correction; **P < 0.01, ****P < 0.001.