Person:

Geha, Raif

DOCK8 and MyD88 have been implicated in serologic memory. Here we report antibody responses were impaired and (CD27^+) memory B cells were severely reduced in DOCK8-deficient patients. Toll-like receptor 9 (TLR9)- but not CD40-driven B cell proliferation and immunoglobulin production were severely reduced in DOCK8-deficient B cells. In contrast, TLR9-driven expression of AICDA, CD23 and CD86, and activation of NF-κB, p38 and Rac1 were intact. DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. Following TLR9 ligation, DOCK8 became tyrosine phosphorylated by Pyk2, bound the Src family kinase Lyn and linked TLR9 to a Src-Syk-STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells.

Patients with a combined immunodeficiency characterized by normal numbers, but impaired function, of T and B cells had a homozygous p.Tyr20His mutation in transferrin receptor 1 (TfR1), encoded by TFRC. The mutation disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 surface expression. Iron citrate rescued the lymphocyte defects and transduction of wild type, but not mutant, TfR1 rescued impaired transferrin uptake in patient fibroblasts. TfrcY20H/Y20H mice recapitulated the patients’ immunologic defects. Despite the critical role of TfR1 in erythrocyte development and function, the patients had only mild anemia and only slightly increased TfR1 expression in erythroid precursors. We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares the patients from severe anemia. These findings demonstrate the importance of TfR1 in adaptive immunity.