This is well in line with observations that complete 4-(Benzyloxy)phenol absence of Pep had no impact on negative selection. Given the lack of impact on thymic selection, we suggest that LYP-W620 might Folinic acid calcium salt pentahydrate primarily act on peripheral T cells. A selective effect of LYP-W620 on signaling in peripheral T cells would be consistent with the observed increase of effector/memory T cells in Pep KO mice. However, a gain of function mutant that increases the activation threshold of effector T cells is difficult to reconcile with auto-immunity. We therefore consider that a peripheral model of promoting auto-immunity through the LYPR620W mutation could involve an impaired Treg function. However, others have not documented diminished Treg function in 619W knock-in mice. Our findings lead us to the conclusion that the mechanism by which LYP-W620 impinges on the immunopathogenesis of T cellmodulated human disease is still uncertain and does not involve major effects on thymocyte-intrinsic processes that establish central tolerance. LYP-W620 might involve yet unknown effects on T cells or it might cause a rather subtle impact that we failed to detect in our experimental systems. One study reported that subjects carrying LYP-W620 have increased numbers of effector T cells. A recent report also suggests that the R620W variation might have unknown “change-in-function” effects on T cells. The LYP-R620W variation might impact the function of other cell types including B cells. It has been suggested that an increased burden of autoreactive B cells �Cperhaps secondary to weakened B cell negative selection�C underlies the predisposition of LYP-W620carrying 
subjects to autoimmune diseases. Zhang et al. found increased activation of dendritic cells in mice carrying a PepR619W knock-in mutation, suggesting that hyperactive myeloid cells also might also contribute to the mechanism of action of the autoimmune predisposing variant. Notably, the complexity and subtlety of LYP-W620 function in myeloid cells likely rivals that of its action in lymphocytes. Our recent work revealed selective loss of capacity to produce type 1 interferon among dendritic cells derived from BACLYPW transgenic mice. Such a myeloid cell defect could contribute to cell-extrinsic aberrations in effector T cells responding to infection or inflammation, yet be consistent with absence of a T cell developmental phenotype for LYP-W620. Our results are supported by experiments in two different mouse transgenic systems and multiple monoclonal and polyclonal TCR transgenic models. However, there are few limitations, including 1) the use of an overexpression system, which is amenable to positional effects, 3) although knock-down and deletion experiments suggest that the function of the phosphatase in TCR signaling is conserved in human and mouse cells, the expression of a human phosphatase in a mouse context can be viewed as another limitation of our model and 4) the use of hybrid mouse strains in some experiments might have decreased the sensitivity to small effects. Despite the above-mentioned limitations, our data strongly suggest that the increased activity of LYP, which �Caccording to several groups�C is conferred by the R620W variation, is insufficient to cause anomalies in thymic selection that could underlie the increased risk of autoimmunity conferred by carriage of the variant. TgLYPW mice transgenic for the active phosphatase variant carried an average calculated phosphatase activity between those reported for heterozygous or homozygous human carriers of the LYP-W620 variant. Since the overall overexpression of the phosphatase was low, the most likely explanation for the lack of a phenotype is that the decrease in thymocyte TCR signaling caused by the overexpression of the phosphatase was too small to significan.