IL-17-committed γδ T (γδT17) cells participate in many immune responses but their developmental requirements and subset specific functions remain poorly understood. Here we report that a commonly used CD45.1+ congenic C57BL/6 mouse substrain is characterized by a selective deficiency in Vγ4+ γδT17 cells. This trait is due to a spontaneous mutation in the transcription factor Sox13 that causes an intrinsic defect in development of these cells in the neonatal thymus. γδT17 cells migrate at low rates from skin to lymph nodes. In a model of psoriasis-like dermatitis, Vγ4+ γδT17 cells expand markedly in lymph nodes and home to inflamed skin. Sox13 mutant mice are protected from psoriasis-like skin changes, identifying a role for Sox13-dependent γδT17 cells in this inflammatory condition.

Gamma delta (γδ) T cells represent a major IL-17 committed T-cell population (γδT17 cells) in the mouse dermis. Following exposure to the inflammatory agent imiquimod (IMQ) the Vγ4 + subset of γδT cells produce IL-17 in the skin and expand rapidly in draining lymph nodes (LNs). Local IMQ treatment in humans is known to exacerbate psoriasis skin lesion activity at distant sites. Whether expanded γδT17 cells sensitize distant sites to inflammation has been unknown. Here we show that expanded Vγ4 + γδT17 cells egress from LNs in a fingolimod (FTY720)-sensitive manner and use C-C chemokine receptor type 2 to accumulate in inflamed skin where they augment neutrophil recruitment and inflammation. They also travel to noninflamed skin and peripheral LNs and remain in elevated numbers at these distant sites for at least 3 mo. Sensitized mice show more rapid skin inflammation and greater proliferation and IL-17 production by Vγ4 + γδT cells upon imiquimod challenge. Transfer experiments confirm that memory-like Vγ4 + γδT17 cells respond more rapidly. Memory-like Vγ4 + γδT17 cells are distinguished by greater IL-1R1 expression and more proliferation in response to IL-1β. These findings establish that local skin inflammation leads to faster and stronger secondary responses to the same stimulus through longterm and systemic changes in the composition and properties of the dermal γδT-cell population.immunological memory | γδT cells | inflammation

Translation initiation factors have complex functions in cells that are not yet understood. We show that depletion of initiation factor eIF4GI only modestly reduces overall protein synthesis in cells, but phenocopies nutrient starvation or inhibition of protein kinase mTOR, a key nutrient sensor. eIF4GI depletion impairs cell proliferation, bioenergetics, and mitochondrial activity, thereby promoting autophagy. Translation of mRNAs involved in cell growth, proliferation, and bioenergetics were selectively inhibited by reduction of eIF4GI, as was the mRNA encoding Skp2 that inhibits p27, whereas catabolic pathway factors were increased. Depletion or overexpression of other eIF4G family members did not recapitulate these results. The majority of mRNAs that were translationally impaired with eIF4GI depletion were excluded from polyribosomes due to the presence of multiple upstream open reading frames and low mRNA abundance. These results suggest that the high levels of eIF4GI observed in many breast cancers might act to specifically increase proliferation, prevent autophagy, and release tumor cells from control by nutrient sensing.

The mTOR signaling complex integrates signals from growth factors and nutrient availability to control cell growth and proliferation, in part through effects on the protein-synthetic machinery. Protein synthesis rates fluctuate throughout the cell cycle but diminish significantly during the G 2 /M transition. The fate of the mTOR complex and its role in coordinating cell growth and proliferation signals with protein synthesis during mitosis remain unknown. Here we demonstrate that the mTOR complex 1 (mTORC1) pathway, which stimulates protein synthesis, is actually hyperactive during mitosis despite decreased protein synthesis and reduced activity of mTORC1 upstream activators. We describe previously unknown G 2 /M-specific phosphorylation of a component of mTORC1, the protein raptor, and demonstrate that mitotic raptor phosphorylation alters mTORC1 function during mitosis. Phosphopeptide mapping and mutational analysis demonstrate that mitotic phosphorylation of raptor facilitates cell cycle transit through G 2 /M. Phosphorylation-deficient mutants of raptor cause cells to delay in G 2 /M, whereas depletion of raptor causes cells to accumulate in G 1 . We identify cyclindependent kinase 1 (cdk1 [cdc2]) and glycogen synthase kinase 3 (GSK3) pathways as two probable mitosisregulated protein kinase pathways involved in mitosis-specific raptor phosphorylation and altered mTORC1 activity. In addition, mitotic raptor promotes translation by internal ribosome entry sites (IRES) on mRNA during mitosis and is demonstrated to be associated with rapamycin resistance. These data suggest that this pathway may play a role in increased IRES-dependent mRNA translation during mitosis and in rapamycin insensitivity.