Dual-specificity phosphatase 6 regulates CD4(+) T-cell functions and restrains spontaneous colitis in IL-10-deficient mice
MUCOSAL IMMUNOLOGY
Authors: Bertin, S.; Lozano-Ruiz, B.; Bachiller, V.; Garcia-Martinez, I.; Herdman, S.; Zapater, P.; Frances, R.; Such, J.; Lee, J.; Raz, E.; Gonzalez-Navajas, J. M.
Abstract
Mitogen-activated protein kinase (MAPK) phosphatases are dual-specificity phosphatases (DUSPs) that dephosphorylate phosphothreonine and phosphotyrosine residues within MAPKs. DUSP6 preferentially dephosphorylates extracellular signal-regulated kinases 1 and 2 (ERK1/2) rendering them inactive. Here, we study the role of DUSP6 in CD4(+) T-cell function, differentiation, and inflammatory profile in the colon. Upon T-cell receptor (TCR) stimulation, DUSP6 knockout (Dusp6(-/-)) CD4(+) T cells showed increased ERK1/2 activation, proliferation, T helper 1 differentiation, and interferon-c production, as well as a marked decrease in survival, interleukin-17A (IL-17A) secretion, and regulatory T-cell function. To analyze the role of DUSP6 in vivo, we employed the Il10(-/-) model of colitis and generated Il10(-/-) /Dusp6(-/-) double-knockout mice. Il10(-/-) /Dusp6(-/-) mice suffered from accelerated and exacerbated spontaneous colitis, which was prevented by ERK1/2 inhibition. ERK1/2 inhibition also augmented regulatory T-cell differentiation in vitro and in vivo in both C57Bl/6 and Dusp6(-/-) mice. In summary, DUSP6 regulates CD4(+) T-cell activation and differentiation by inhibiting the TCR-dependent ERK1/2 activation. DUSP6 might therefore be a potential intervention target for limiting aberrant T-cell responses in T-cell-mediated diseases, such as inflammatory bowel disease.
Human Bone Marrow-Resident Natural Killer Cells Have a Unique Transcriptional Profile and Resemble Resident Memory CD8(+) T Cells
FRONTIERS IN IMMUNOLOGY
Authors: Melsen, Janine E.; Lugthart, Gertjan; Vervat, Carly; Kielbasa, Szymon M.; van der Zeeuw, Sander A. J.; Buermans, Henk P. J.; van Ostaijen-ten Dam, Monique M.; Lankester, Arjan C.; Schilham, Marco W.
Abstract
Human lymphoid tissues harbor, in addition to CD56(bright) and CD56(dim) natural killer (NK) cells, a third NK cell population: CD69(+)CXCR6(+) lymphoid tissue (lt) NK cells. The function and development of ltNK cells remain poorly understood. In this study, we performed RNA sequencing on the three NK cell populations derived from bone marrow (BM) and blood. In ltNK cells, 1,353 genes were differentially expressed compared to circulating NK cells. Several molecules involved in migration were downregulated in ltNK cells: S1PR1, SELPLG and CD62L. By flow cytometry we confirmed that the expression profile of adhesion molecules (CD49e(-), CD29(low), CD81(high), CD62L(-), CD11c(-)) and transcription factors (Eomes(high), Tbet(low)) of ltNK cells differed from their circulating counterparts. LtNK cells were characterized by enhanced expression of inhibitory receptors TIGIT and CD96 and low expression of DNAM1 and cytolytic molecules (GZMB, GZMH, GNLY). Their proliferative capacity was reduced compared to the circulating NK cells. By performing gene set enrichment analysis, we identified DUSP6 and EGR2 as potential regulators of the ltNK cell transcriptome. Remarkably, comparison of the ltNK cell transcriptome to the published human spleen-resident memory CD8(+) T (Trm) cell transcriptome revealed an overlapping gene signature. Moreover, the phenotypic profile of ltNK cells resembled that of CD8(+) Trm cells in BM. Together, we provide transcriptional and phenotypic data that clearly distinguish ltNK cells from both the CD56(bright) and CD56(dim) NK cells and substantiate the view that ltNK cells are tissue-resident cells, which are functionally restrained in killing and have low proliferative activity.
COA
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