Protein kinase C theta is required for efficient induction of IL-10-secreting T cells.
Secretion of interleukin-10 (IL-10) by CD4+ T cells is an essential immunoregulatory mechanism. The work presented here assesses the role of the signaling molecule protein kinase C theta (PKCθ) in the induction of IL-10 expression in CD4+ T cells. Using wildtype and PKCθ-deficient Tg4 T cell receptor transgenic mice, we implemented a well-described protocol of repeated doses of myelin basic protein (MBP)Ac1-9[4Y] antigen to induce Tr1-like IL-10+ T cells. We find that PKCθ is required for the efficient induction of IL-10 following antigen administration. Both serum concentrations of IL-10 and the proportion of IL-10+ T cells were reduced in PKCθ-deficient mice relative to wildtype mice following [4Y] treatment. We further characterized the T cells of [4Y] treated PKCθ-deficient Tg4 mice and found reduced expression of the transcription factors cMaf, Nfil3 and FoxP3 and the surface receptors PD-1 and Tim3, all of which have been associated with the differentiation or function of IL-10+ T cells. Finally, we demonstrated that, unlike [4Y] treated wildtype Tg4 T cells, cells from PKCθ-deficient mice were unable to suppress the priming of naïve T cells in vitro and in vivo. In summary, we present data demonstrating a role for PKCθ in the induction of suppressive, IL-10-secreting T cells induced in TCR-transgenic mice following chronic antigen administration. This should be considered when contemplating PKCθ as a suitable drug target for inducing immune suppression and graft tolerance.
School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
Graham J
GJ
Britton
School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
Ruth E
RE
Mitchell
School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
Bronwen R
BR
Burton
School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
David C
http://orcid.org/0000-0003-2147-5614
DC
Wraith
D000818:Animals; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D005260:Female; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000097:blood / Q000378:metabolism*; D007527:Isoenzymes / Q000502:physiology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000276:immunology; D011493:Protein Kinase C / Q000502:physiology*; D000074121:Protein Kinase C-theta; D015398:Signal Transduction
D015415:Biomarkers; C556062:IL10 protein, mouse; D007527:Isoenzymes; D004676:Myelin Basic Protein; D016753:Interleukin-10; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta