A number of phenotypic similarities between JNK1−/− T cells and T

A number of phenotypic similarities between JNK1−/− T cells and Tat-POSH-treated cells were also observed. Tat-POSH-treated T cells have defective CD25 expression and cell cycle entry. They make negligible amounts of IL-2 and showed no changes in granzyme B, in stark contrast to JNK2−/− CD8+ T cells [16, 17, 19]. The effector cytokine expression profile also more closely resembles JNK1−/− than JNK2−/− T cells [13, 16, 17,

44]. Interestingly, the disruption of the POSH/JIP-1 complex for the first 48 h of activation led to a defect in the program of differentiation that resulted in a persistent deficiency in the Veliparib supplier effector response even after the ability to disrupt the complex is lost. Remarkably, T cells activated in the presence of the inhibitor for only 2 days maintained their defect throughout an antitumor immune response in vivo. Furthermore, addition of the inhibitor 2 days poststimulation had no effect. Thus, the POSH-dependent commitment to IFN-γ is programed in the first 48 h. This suggests a role (direct or indirect) for the POSH/JIP-1 network in the transcriptional regulation of epigenetic modifications necessary for the early development of T-cell effector functions. Confirmation of selleck kinase inhibitor the programing defect

was evident from the decrease in the phosphorylation of c-Jun, defects in the induction of T-bet, Eomes, and reduced effector cytokine production. JNK1 induces the phosphorylation of c-Jun and leads to increases in the mRNA expression Lonafarnib of both

T-bet and Eomes [18, 42]. Conversely, JNK2 is a negative regulator of T-bet and Eomes mRNA expression [19]. Along these lines, the protein levels of Eomes were not induced above background in the presence of Tat-POSH. Intriguingly, protein expression of T-bet in CD8+ T cells was low early but recovered at later time points. Whether this is due to changes in the POSH/JIP-1 complex or other cause is not known. These data differ slightly from previous work where JNK1 deficiency had a greater impact on T-bet than Eomes [19]. Surprisingly, Perforin expression, which is defective in JNK1−/− CD8+ T cells [18], was only slightly affected by disruption of POSH/JIP-1 complex. This was also unexpected, as Eomes deficiency has been linked to the reduction of perforin mRNA expression [42]. The differences between these and earlier works may be attributed to the methods of quantification (mRNA versus protein) and relative stability of these two proteins. Alternatively, they suggest a role for JNK in expression of these effector molecules and transcription factors that does not involve the formation of the POSH/JIP-1 complex. Interestingly, the ability to disrupt the complex with Tat-POSH diminishes over time. This indicates that the composition or configuration of the POSH/JIP1 complex changes over the course of the immune response.

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