Protein kinase C theta is critical for the development of in vivo T helper (Th)2 cell but not Th1 cell responses.
The serine/threonine-specific protein kinase C (PKC)-theta is predominantly expressed in T cells and localizes to the center of the immunological synapse upon T cell receptor (TCR) and CD28 signaling. T cells deficient in PKC-theta exhibit reduced interleukin (IL)-2 production and proliferative responses in vitro, however, its significance in vivo remains unclear. We found that pkc-theta(-/-) mice were protected from pulmonary allergic hypersensitivity responses such as airway hyperresponsiveness, eosinophilia, and immunoglobulin E production to inhaled allergen. Furthermore, T helper (Th)2 cell immune responses against Nippostrongylus brasiliensis were severely impaired in pkc-theta(-/-) mice. In striking contrast, pkc-theta(-/-) mice on both the C57BL/6 background and the normally susceptible BALB/c background mounted protective Th1 immune responses and were resistant against infection with Leishmania major. Using in vitro TCR transgenic T cell-dendritic cell coculture systems and antigen concentration-dependent Th polarization, PKC-theta-deficient T cells were found to differentiate into Th1 cells after activation with high concentrations of specific peptide, but to have compromised Th2 development at low antigen concentration. The addition of IL-2 partially reconstituted Th2 development in pkc-theta(-/-) T cells, consistent with an important role for this cytokine in Th2 polarization. Taken together, our results reveal a central role for PKC-theta signaling during Th2 responses.
Marsland
Benjamin J
BJ
Molecular Biomedicine, Swiss Federal Institute of Technology, Wagistr. 27, CH8952 Zurich-Schlieren, Switzerland.
Soos
Timothy J
TJ
Späth
Gerald
G
Littman
Dan R
DR
Kopf
Manfred
M
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D018106:CD28 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation; D002455:Cell Division; D002469:Cell Separation; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology*; D018320:Leishmania major / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010455:Peptides / Q000737:chemistry; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D000074121:Protein Kinase C-theta; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000378:metabolism*; D018418:Th2 Cells / Q000378:metabolism*; D019076:Transgenes
D018106:CD28 Antigens; D016207:Cytokines; D007376:Interleukin-2; D007527:Isoenzymes; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D015847:Interleukin-4; D007371:Interferon-gamma; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta