IL-21 is the primary common γ chain-binding cytokine required for human B-cell differentiation in vivo.
SCID resulting from mutations in IL2RG or JAK3 is characterized by lack of T and natural killer cells; B cells are present in normal number, but antibody responses are defective. Hematopoietic cell transplantation (HCT) is curative for SCID. However, B-cell dysfunction persists in a substantial proportion of patients. We hypothesized that impaired B-cell responses after HCT in IL2RG/JAK3 deficiency results from poor donor B-cell engraftment and defective γc-dependent cytokine signaling in host B cells. To test this, and to identify which γc cytokine(s) is critical for humoral immunity, we studied 28 transplanted patients with IL2RG/JAK3 deficiency. Lack of donor B-cell engraftment associated with persistent humoral dysfunction and significantly reduced memory B cells. B-cell proliferation induced by CD40L alone or together with CpG, anti-Ig, IL-4, IL-10, or IL-13 was comparable in healthy controls and in post-HCT SCID patients, irrespective of their chimerism status. However, in vitro stimulation with CD40L/IL-21 induced B-cell proliferation, plasmablast differentiation, and antibody secretion in patients with donor B cells, but not in patients with autologous B cells. These data imply that IL-21-mediated signaling is critical for long-lived humoral immunity and to restore antibody responses in IL2RG/JAK3-deficient patients after HCT. Furthermore, in vitro stimulation with CD40L/IL-21 can predict in vivo B-cell immunity in IL2RG/JAK3 SCID after transplantation.
Division of Immunology, Children's Hospital, Harvard Medical School, Boston, MA, USA.
Mike
M
Recher
Lucinda J
LJ
Berglund
Danielle T
DT
Avery
Morton J
MJ
Cowan
Andrew R
AR
Gennery
Joanne
J
Smart
Jane
J
Peake
Melanie
M
Wong
Sung-Yun
SY
Pai
Sachin
S
Baxi
Jolan E
JE
Walter
Umaimainthan
U
Palendira
Gillian A
GA
Tangye
Michael
M
Rice
Shannon
S
Brothers
Waleed
W
Al-Herz
Hans
H
Oettgen
Hermann
H
Eibel
Jennifer M
JM
Puck
Federica
F
Cattaneo
John B
JB
Ziegler
Silvia
S
Giliani
Stuart G
SG
Tangye
Luigi D
LD
Notarangelo
D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D053616:Janus Kinase 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053632:X-Linked Combined Immunodeficiency Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000098546:Interleukin-21
D007070:Immunoglobulin A; D007075:Immunoglobulin M; D053631:Interleukin Receptor Common gamma Subunit; D007378:Interleukins; D023201:CD40 Ligand; C507933:JAK3 protein, human; D053616:Janus Kinase 3; D000098546:Interleukin-21