Protein kinase C θ (PKC θ) is a serine/threonine kinase that is now firmly established
as a central component in T cell activation, proliferation, differentiation, and apoptosis
(Hayashi and Altman, 2007). Since it was first discovered that PKC θ re-localizes
to the immunological synapse (IS) in conventional effector T cells following T cell
stimulation, many roles have now been defined for this kinase in these cells such
as (a) activation of NF-κB, AP-1, and NFAT transcription factors that control the
synthesis of pro-inflammatory cytokines and the anti-apoptotic molecule Bcl-xL (Hayashi
and Altman, 2007), (b) regulation of IS dynamics (Sims et al., 2007), (c) up-regulation
and clustering of the integrin LFA-1 on the T cell surface (Tan et al., 2006; Letschka
et al., 2008) – thus facilitating stable adhesion between T cells and antigen-presenting
cells (APC) and/or migration into inflamed tissues, (d) re-orientation of the microtubule-organizing
center toward the APC (Quann et al., 2011), and (e) fine tuning of T cell activation
by regulating the intracellular localization, degradation, and internalization of
key signaling molecules (Nika et al., 2006; von Essen et al., 2006; Gruber et al.,
2009). A new function for PKC θ has also recently been revealed with the finding that
this kinase regulates an inducible gene expression program in T cells by associating
with chromatin in the nucleus (Sutcliffe et al., 2011).
A host of studies have now convincingly demonstrated that targeting PKC θ could be
a viable therapeutic strategy to block the T cell inflammatory response in autoimmunity,
allergy, and allograft rejection (Marsland and Kopf, 2008; Zanin-Zhorov et al., 2011;
Altman and Kong, 2012). For example, PKC θ-deficient mice (PKC θ−/−) have reduced
incidence and severity of Th2 and Th17-mediated inflammatory disorders, including
asthma, inflammatory bowel disease, multiple sclerosis, arthritis, and allograft rejection
in comparison to their wild-type littermates (PKC θ+/+; Marsland and Kopf, 2008; Zanin-Zhorov
et al., 2011; Altman and Kong, 2012). Intriguingly, PKCθ−/− mice are still capable
of mounting relatively normal Th1 and CD8+ T cell-mediated immune responses to infectious
viruses (Marsland and Kopf, 2008; Zanin-Zhorov et al., 2011; Altman and Kong, 2012).
Secondly, the recent finding that inhibition of PKC θ increases the suppressive activity
of regulatory T cells (Zanin-Zhorov et al., 2010) suggests that therapeutic strategies
designed to inhibit this kinase may hold great promise in diverting the pro/anti-inflammatory
balance toward a reduction in inflammation in T cell autoimmunity and allergy, whilst
at the same time maintaining immunity to viral pathogens. Lastly, that PKC θ has a
restricted tissue expression profile and is highly expressed in T cells suggests that
targeting this molecule with specific inhibitors should have minimal effects in other
cells and tissues (Hayashi and Altman, 2007; Altman and Kong, 2012). In spite of all
this promising data however, a number of studies have demonstrated that targeting
PKC θ could potentially have some undesired effects. For example, it has been reported
that CD8+ T cells from PKC θ−/− mice have a survival defect following activation (Barouch-Bentov
et al., 2005; Saibil et al., 2007; Kingeter and Schaefer, 2008). In addition, it has
been reported that PKC θ−/− mice have an impaired anti-leukemic response (Garaude
et al., 2008), which likely results from reduced tumor surveillance in vivo. It is
important therefore that these issues are addressed in respect of any PKC θ-targeting
strategies that are developed in the future.
Although much has been learned about PKC θ in T cells, considerable gaps still exist
in our knowledge as to how this kinase is regulated, including the upstream signals
and interacting partners that control its intracellular localization and catalytic
activation at various locations in the cell. Furthermore, although a plethora of substrates
that are phosphorylated by PKC θ in vitro have now been characterized (Nika et al.,
2006; Hayashi and Altman, 2007; Letschka et al., 2008), whether any of these are bona
fide substrates in vivo remains to be addressed. Like many other kinases, PKC θ is
also regulated by phosphorylation on a host of serine, threonine, and tyrosine residues
that influence its activity and intracellular localization. Six phosphorylation sites
have been mapped on PKC θ in T cells to date. Some of these sites appear to be phosphorylated
by unrelated upstream kinases, while other sites are regulated via auto-phosphorylation.
Three of these phosphorylation sites are highly conserved on most other PKC isoforms,
which suggests that they may regulate aspects that are central to all isoforms, such
as stability. In contrast, PKC θ contains three phosphorylation sites that appear
to be unique to this isoform.1 Therefore PKC θ may execute distinct functions and/or
be regulated differently in T cells (Freeley et al., 2011). In this issue of Frontiers
in T Cell Biology, Wang et al. (2012) summarize the regulation of PKC θ by phosphorylation
during T cell signaling. Understanding the pathways that regulate PKC θ in T cells
may provide additional therapeutic targets for the treatment of inflammatory diseases.