This may possibly be due to a shortened G1 phase caused by DPP2 kd, an observation that we made in DPP2 kd fibroblasts, which proliferate faster than WT cells in the presence of serum (unpublished result). Similarly, it has been reported that T cells lacking transactivator of ErbB2 (TOB1) have a reduced threshold of activation 34. Furthermore,

loss of Lung-Kruppel-like PLX4032 molecular weight factor 2 (KLF2) leads to a loss of quiescence defined by proliferation, increased metabolism and altered expression of activation markers 35. Interestingly, we previously demonstrated that DPP2 is transcriptionally activated by KLF2 and TOB1, linking them in a program that maintains lymphocyte quiescence, which is regulated by quiescence-specific transcription 3. Collectively, these data support the role of DPP2 in preventing proliferation and promoting quiescence. selleck chemicals Of particular interest is the finding that naïve T cells from lck-DPP2 kd mice mainly produce IL-17, the signature cytokine of Th17 cells 36, upon TCR-mediated activation in vitro. In addition, these cells significantly upregulate rorγt mRNA, the master

regulator of Th17 differentiation 15. In agreement with this observation, we found that IL-2 and IFN-γ production was downregulated in the activated mutant T cells. CD4+ and CD8+ T cells respectively, produce these cytokines after TCR activation in the absence of exogenous

factors. Furthermore, IL-2 has been shown to induce Foxp3 expression and inhibit Th17-cell differentiation 37. Collectively, our data support the notion that loss of DPP2 causes T cells to differentiate into Th17 cells and IL-17 producing CD8+ T cells upon TCR stimulation. It can be surmised from these results that the out production of the inflammatory cytokine IL-17 is the default pathway in T-cell differentiation and is actively suppressed by DPP2. Such a control may be important to prevent expansion of autoreactive T cells. In agreement with this hypothesis, we observed increased levels of ANA in the lck-DPP2 kd mice, indicative of augmented autoantibody production in these mice. Th17 cells have been implicated in numerous human diseases, such as psoriasis, rheumatoid arthritis, multiple sclerosis, asthma and some bacterial and fungal infections 38. A recent report on the effects of the loss of early growth response gene-2 in T cells suggests that autoimmune disorders can result from a loss of effector T-cell expansion and inflammatory activation 39. This is consistent with the observations made in lck-DPP2 kd mice, where T cells are hyper-proliferative and differentiate into IL-17-producing cells. Several other reports have also shown examples of proteins that act to prevent abnormal T-cell proliferation and autoimmunity associated with the production of IL-17.