Loss of PKCλ/ι impairs Th2 establishment and allergic airway inflammation in vivo

Abstract

The differentiation of T cells along different lineages is central to the control of immunity. Here we have used a conditional gene knockout system to delete PKC / selectively in activated T cells. With this system we have demonstrated that PKC / is necessary for T-helper cell (Th2) cytokine production and optimal T-cell proliferation and allergic airway inflammation in vivo. Our data demonstrate that the activation of the transcription factors nuclear factor of activated T cells and NF-B is impaired in PKC / -deficient activated T cells. In addition, we present genetic knockout evidence in ex vivo experiments with primary T cells that PKC / is critical for the control of cell polarity during T-cell activation. Therefore PKC / emerges as a critical regulator of Th 2 activation.Asthma ͉ NF-kappaB ͉ T-cell activation ͉ polarity ͉ NF-AT

Atypical protein kinase C (aPKCζ and aPKCλ) is dispensable for mammalian hematopoietic stem cell activity and blood formation

“…This finding suggests that the existence of aPKCζ-and aPKCλ-dependent stem cell polarity is not a functional determinant for mammalian HSC activity. Conversely, aPKC signaling is implicated in the regulation of mammalian T-cell activity (12,13), indicating that the contribution of aPKCζ/λ signaling in mammalian HSCs and in terminally differentiated cells is functionally distinguishable. These data underscore the importance of cell, tissue-microenvironment, and context-dependent regulation of evolutionary conserved signaling pathways.…”

“…Classical cell-polarity complex proteins consist of partitioning-defective proteins: Par3, Par6, and atypical protein kinase C (aPKCζ and aPKCλ) (7). In the hematopoietic system, aPKC signaling has been implicated in the establishment of T-cell polarity during immunological synapse and in the regulation of pathogen-specific CD8 + T-cell activity (12,13). aPKCs have been shown to play a crucial role in Drosophila neuroblast self-renewal and differentiation (4,8,14,15).…”

“…Whether stem cell activity is truly dependent on asymmetric cell division remains controversial (1). Distinct polarity proteins have been shown to act as core components of the cell polarization machinery in animals ranging from Caenorhabditis elegans to humans (6)(7)(8)(9)(10)(11)(12). Asymmetric cell division requires polar distribution of a set of proteins that accumulate before mitosis.…”

Reciprocal Regulation of Protein Kinase C Isoforms Results in Differential Cellular Responsiveness

“…Members of the PKC family are activated by membrane receptor-triggered signals, and the activated PKCs are involved in a wide range of crucial cellular functions, implying their indispensability (6)(7)(8). Paradoxically, excepting PKCl, none of the other PKC isoform-deficient mice is embryonically lethal, raising questions about the nonredundancy for these PKC isoforms in physiological regulation of membrane receptor-triggered cellular effector functions (6,9). Moreover, relative roles for particular cell-expressed PKC isoforms in receptor-triggered cellular functions have never been addressed.…”

A conundrum in mammalian hematopoietic stem cell polarity

“…This suggests that aPKCζ and aPKCλ-dependent stem cell polarity, if any, cannot be a functional determinant for mammalian HSC activity. However, in contrary to the dispensable function of aPKCs in mammalian HSC, aPKCλ has been shown to function as a positive regulator for T cells in the establishment of immunological synapse 7 and fate choice between effector and memory T cells. 8 Therefore, the contribution of aPKCζ/λ signaling in mammalian HSCs and in terminally differentiated cells is functionally distinguishable, and it underscores the importance of cell-, tissue microenvironment-and context-dependent regulation of evolutionarily conserved signaling pathways.…”