Protein Kinase C θ Is Critical for the Development of In Vivo T Helper (Th)2 Cell But Not Th1 Cell Responses

Abstract

The serine/threonine-specific protein kinase C (PKC)-θ 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-θ exhibit reduced interleukin (IL)-2 production and proliferative responses in vitro, however, its significance in vivo remains unclear. We found that pkc-θ− / − 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-θ− / − mice. In striking contrast, pkc-θ− / − 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-θ–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-θ− / − T cells, consistent with an important role for this cytokine in Th2 polarization. Taken together, our results reveal a central role for PKC-θ signaling during Th2 responses.

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

“…8 PKC-is expressed in T cells and is a key component of T-cell receptor signaling and activation. 12,13,33,34 However, PKC--dependent pathways are differently required in T-cell activation and are especially critical for development of Th2 but not Th1 cells. 12,13 PKC-is not essential for T-cell activation leading to viral clearance.…”

“…Among the PKC family, PKC-␦ and PKC-are expressed in lymphocytes, and PKC-is also expressed in natural killer cells. 11 PKC-is a critical regulator of T-cell receptor signaling and T-cell activation, 12,13 and has been proposed as a therapeutic target for T-cell-mediated diseases. 12 However, the role of PKC-in T-cell activation is complex, and PKC-is not equally involved in all T-cell responses.…”

“…PKC-regulates Th2 helper cells that mediate immune response against helminth infection. 12,13 It is involved in interferon I and II signaling in human T cells. 14 PKC-is also important for T-cell survival and differentiation into functional cytotoxic T cells; however, it may be dispensable, compensated by other innate signals, for CD8 ϩ T-cell proliferation and development.…”

Resistance to Experimental Autoimmune Encephalomyelitis and Impaired IL-17 Production in Protein Kinase Cθ-Deficient Mice

“…In an asthmatic lung inflammation model, Th2 immune responses were preferentially impaired in the absence of PKC without a profound defect in Th1 responses in lung, even though PKC was required for the initial development of Th1 cells (18). Furthermore, PKC Ϫ/Ϫ mice were able to mount a normal protective Th1 response against Leishmania major infection, but not a Th2 response to Nippostrongylus brasiliensis (19), indicating that PKC preferentially modulates Th2 immune responses. However, it is not clear whether PKC plays any role in autoimmune disease conditions in which Th1/ IL-17 responses predominate.…”

“…Recent studies provide some evidence that PKC is involved not only in T cell activation, but also in Th1/Th2 differentiation under different inflammatory conditions in vivo (18,19). However, little is known about the role of PKC in T cell production of IL-17 and Th17 differentiation.…”