IL2RG mutant naive B cells fail to proliferate in response to IL-21. (A) Naive B cells from control donors (n = 15) or transplanted X-SCID/JAK3–deficient patients with either donor-derived (group 1; n = 6) or autologous (group 2; n = 7) B cells were stimulated with CD40L alone or together with anti-Ig, CpG, IL-4, IL-10, IL-13, IL-15, or IL-21. Proliferation was determined after 5 days by measuring incorporation of [³H]thymidine during the final 18 hours of culture. The results are expressed as fold-change in proliferation relative to CD40L alone. [³H]Thymidine uptake (mean cpm ± SEM) by naive B cells isolated from healthy donors (n = 15), group 1 (n = 6), or group 2 (n = 7) transplanted X-SCID/JAK3–deficient patients who were stimulated with CD40L alone was 393 ± 63, 419 ± 104, and 442 ± 71, respectively. (B-C) Naive B cells from control donors or transplanted group 1 (B) or group 2 (C) X-SCID/JAK3–deficient patients were labeled with CFSE and then cultured with CD40L alone or together with IL-4 or IL-21. Proliferation, as determined by dilution of CFSE, was measured after 5 days of culture. Data from experiments that examined responses of naive B cells from 3 different group 2 X-SCID patients is presented in panel C.