Differential requirement of PKC-theta in the development and function of natural regulatory T cells.
CD4+CD25+ natural Treg cells, which are developed in the thymus, migrate to the periphery to actively maintain self-tolerance. Similar to conventional T cells, TCR signals are critical for the development and activation of Treg cell inhibitory function. While PKC-theta-mediated TCR signals are required for the activation of peripheral naïve T cells, they are dispensable for their thymic development. Here, we show that mice deficient in PKC-theta had a greatly reduced number of CD4+Foxp3+ Treg cells, which was independent of PKC-theta-regulated survival, as transgenic Bcl-x(L) could not restore the Treg cell population in PKC-theta(-/-) mice. Active and WT PKC-theta markedly stimulated, whereas inactive PKC-theta and dominant negative NFAT inhibited Foxp3 promoter activity. In addition, mice-deficient in calcineurin Abeta had a decreased Treg cell population, similar to that observed in PKC-theta deficient mice. It is likely that PKC-theta promoted the development of Treg cells by enhancing Foxp3 expression via activation of the calcineurin/NFAT pathway. Finally, Treg cells deficient in PKC-theta were as potent as WT Treg cells in inhibiting T cell activation, indicating that PKC-theta was not required for Treg cell-mediated inhibitory function. Our data highlight the contrasting roles PKC-theta plays in conventional T cell and natural Treg cell function.
Department of Microbiology & Immunology, School of Medicine, University of Illinois, Chicago, IL 60612, USA.
Sonal
S
Gupta
Santhakumar
S
Manicassamy
Chenthamarakshan
C
Vasu
Anvita
A
Kumar
Weirong
W
Shang
Zuoming
Z
Sun
D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000074121:Protein Kinase C-theta; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology*; D013950:Thymus Gland / Q000201:enzymology / Q000276:immunology
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007527:Isoenzymes; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D019703:Calcineurin