An immunodeficiency characterized by defective signal transduction in T lymphocytes.
We studied a nine-year-old boy with severe, recurrent infections. The patient was exposed in utero to azathioprine and prednisone. He had autoimmune hemolytic anemia, bronchiectasis, and Hodgkin's disease. The patient's circulating lymphocytes were normal in number and phenotype, but stimulation of the T-cell receptor by antigens, mitogens, and monoclonal antibodies failed to induce interleukin-2-receptor expression, interleukin-2 synthesis, or lymphocyte proliferation. The early biochemical events necessary to initiate lymphocyte activation--accumulation of the second messenger diacylglycerol, activation of the enzyme protein kinase C, and elevation of the free intracellular calcium concentration--failed to occur in this patient's lymphocytes. The defect in the lymphocyte could be corrected in vitro by two agents that bypass the receptor-mediated signal mechanism (the diacylglycerol analogue phorbol and the calcium ionophore ionomycin). Further studies localized the defect in signal transduction to the interaction between cell-surface receptors and the guanine nucleotide-binding protein. We conclude that this patient's immunodeficiency was caused by a defective coupling of surface receptors to signal-transducing proteins in his T lymphocytes, resulting in failure of lymphocyte activation.
Chatila
T
T
Division of Immunology, Children's Hospital, Boston, MA 02115.
Wong
R
R
Young
M
M
Miller
R
R
Terhorst
C
C
Geha
R S
RS
D002118:Calcium / Q000097:blood; D002648:Child; D004075:Diglycerides / Q000097:blood; D004789:Enzyme Activation; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000209:etiology*; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008297:Male; D010712:Phosphatidic Acids / Q000097:blood; D011493:Protein Kinase C / Q000097:blood; D015375:Receptors, Interleukin-2 / Q000032:analysis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*
D004075:Diglycerides; D007376:Interleukin-2; D010712:Phosphatidic Acids; D015375:Receptors, Interleukin-2; D011493:Protein Kinase C; D002118:Calcium