X-SCID B cell responses to interleukin-4 and interleukin-13 are mediated by a receptor complex that includes the interleukin-4 receptor alpha chain (p140) but not the gamma c chain.
This study investigates the effect of interleukin (IL)-4 mutant proteins and a monoclonal antibody to the IL-4 receptor alpha chain on IL-4 and IL-13 response by B cells from X-linked severe combined immunodeficiency (X-SCID) patients in which the common gamma chain (gamma c chain) gene mutations have been fully characterized and no gamma c chain expression was detected. In this gamma c chain gene knockout model, it was confirmed that the gamma c 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 gamma c 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 alpha 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 alpha chain but not the gamma c chain. Another mutant protein, IL-4(R88D), which has greatly reduced affinity for IL-4R alpha, 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 gamma c 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 alpha chain associated with the recently cloned IL-13R binding protein. This model has major implications for understanding normal B cell responses to IL-4.
Matthews
D J
DJ
Immunobiology Unit, Institute of Child Health, London, GB.
Hibbert
L
L
Friedrich
K
K
Minty
A
A
Callard
R E
RE
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000502:physiology*; D001402:B-Lymphocytes / Q000276:immunology*; D007153:Immunologic Deficiency Syndromes / Q000276:immunology*; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D046911:Macromolecular Substances; D051379:Mice; D016513:Mice, SCID / Q000276:immunology*; D011971:Receptors, Immunologic / Q000502:physiology; D018123:Receptors, Interleukin / Q000737:chemistry / Q000502:physiology*; D019948:Receptors, Interleukin-4; D015398:Signal Transduction; D014960:X Chromosome
D015703:Antigens, CD; D018793:Interleukin-13; D046911:Macromolecular Substances; D011971:Receptors, Immunologic; D018123:Receptors, Interleukin; D019948:Receptors, Interleukin-4; D015847:Interleukin-4