X-SCID B cell responses to interleukin-4 and interleukin-13 are mediated by a receptor complex that includes the interleukin-4 receptor α chain (p140) but not the γ chain

This study investigates the effect of interleukin (IL)-4 mutant proteins and a monoclonal antibody to the IL-4 receptor α chain on IL-4 and IL-13 response by B cells from X-linked severe combined immunodeficiency (X-SCID) patients in which the common γ chain (γc chain) gene mutations have been fully characterized and no γc chain expression was detected. In this γc chain gene knockout model, it was confirmed that the γc chain is essential for B cell responses to IL-2 but not for IL-4 or IL-13. Dose-response curves for X-SCID and normal B cell responses to IL-4 were indistinguishable, showing that the loss of the γc chain did not diminish the sensitivity of B cells to IL-4. The mutant protein IL-4_Y124D and an antibody to the IL-4R α chain both inhibited responses of X-SCID B cells to IL-4 and IL-13, showing that X-SCID B cell responses to these cytokines are mediated by a receptor complex that includes the IL-4R α chain but not the γc chain. Another mutant protein, IL-4_R88D, which has greatly reduced affinity for IL-4Rα, was found to inhibit responses by normal B cells to IL-4 but not to IL-13. IL-4_R88D did not, however, inhibit X-SCID B cell responses to IL-4. This result is consistent with IL-4_R88D inhibition of responses mediated by receptor complexes that include the γc chain. We propose that X-SCID B cells responses to IL-4 are mediated by an IL-13 receptor complex comprised of the IL-4R α chain associated with the recently cloned IL-13R binding protein. This model has major implications for understanding normal B cell responses to IL-4.