PKC-theta selectively controls the adhesion-stimulating molecule Rap1.
The antigen-specific interaction of a T cell with an antigen-presenting cell (APC) results in the formation of an immunologic synapse (IS) between the membranes of the 2 cells. beta(2) integrins on the T cell, namely, leukocyte function-associated antigen 1 (LFA-1) and its counter ligand, namely, immunoglobulin-like cell adhesion molecule 1 (ICAM-1) on the APC, critically stabilize this intercellular interaction. The small GTPase Rap1 controls T-cell adhesion through modulating the affinity and/or spatial organization of LFA-1; however, the upstream regulatory components triggered by the T-cell receptor (TCR) have not been resolved. In the present study, we identified a previously unknown function of a protein kinase C- theta (PKC-theta)/RapGEF2 complex in LFA-1 avidity regulation in T lymphocytes. After T-cell activation, the direct phosphorylation of RapGEF2 at Ser960 by PKC- theta regulates Rap1 activation as well as LFA-1 adhesiveness to ICAM-1. In OT-II TCR-transgenic CD4(+) T cells, clustering of LFA-1 after antigen activation was impaired in the absence of PKC- theta. These data define that, among other pathways acting on LFA-1 regulation, PKC- theta and its effector RapGEF2 are critical factors in TCR signaling to Rap1. Taken together, PKC- theta sets the threshold for T-cell activation by positively regulating both the cytokine responses and the adhesive capacities of T lymphocytes.
Letschka
Thomas
T
Department for Medical Genetics, Innsbruck Medical University, Innsbruck, Austria.
Kollmann
Veronika
V
Pfeifhofer-Obermair
Christa
C
Lutz-Nicoladoni
Christina
C
Obermair
Gerald J
GJ
Fresser
Friedrich
F
Leitges
Michael
M
Hermann-Kleiter
Natascha
N
Kaminski
Sandra
S
Baier
Gottfried
G
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics*; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019169:Jurkat Cells; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000074121:Protein Kinase C-theta; D034741:RNA, Small Interfering / Q000494:pharmacology; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; D007527:Isoenzymes; D016169:Lymphocyte Function-Associated Antigen-1; D009419:Nerve Tissue Proteins; C403525:RAPGEF2 protein, human; D034741:RNA, Small Interfering; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D020827:rap1 GTP-Binding Proteins