Regulated movement of CD4 in and out of the immunological synapse.
The mechanism underlying the transient accumulation of CD4 at the immunological synapse (IS) and its significance for T cell activation are not understood. To investigate these issues, we mutated a serine phosphorylation site (S408) in the cytoplasmic tail of murine CD4. Preventing phosphorylation of S408 did not block CD4 recruitment to the IS; rather, it blocked the ability of CD4 to leave the IS. Surprisingly, enhanced and prolonged CD4 accumulation at the supramolecular activation cluster in the contact area had no functional consequence for T cell activation, cytokine production, or proliferation. Protein kinase C theta (PKCtheta)-deficient T cells also displayed enhanced and prolonged accumulation of wild-type CD4 at the IS, indicating that theta is the critical PKC isoform involved in CD4 movement. These findings suggest a model wherein recruitment of CD4 to the IS allows its phosphorylation by PKCtheta and subsequent removal from the IS. Thus, an important role for PKCtheta in T cell activation involves its recruitment to the IS, where it phosphorylates specific substrates that help to maintain the dynamism of protein turnover at the IS.
Kao
Henry
H
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Lin
Joseph
J
Littman
Dan R
DR
Shaw
Andrey S
AS
Allen
Paul M
PM
D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D005822:Genetic Vectors; D054992:Immunological Synapses / Q000235:genetics / Q000276:immunology; D007527:Isoenzymes / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D000074121:Protein Kinase C-theta; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D012694:Serine / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism
D015704:CD4 Antigens; D016207:Cytokines; D007527:Isoenzymes; D012694:Serine; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D000409:Alanine