DOCK8 is essential for T-cell survival and the maintenance of CD8+ T-cell memory

Deficiency in the guanine nucleotide exchange factor dedicator of cytokinesis 8 (DOCK8) causes a human immunodeficiency syndrome associated with recurrent sinopulmonary and viral infections. We have recently identified a DOCK8‐deficient mouse strain, carrying an ethylnitrosourea‐induced splice‐site mutation that shows a failure to mature a humoral immune response due to the loss of germinal centre B cells. In this study, we turned to T‐cell immunity to investigate further the human immunodeficiency syndrome and its association with decreased peripheral CD4⁺ and CD8⁺ T cells. Characterisation of the DOCK8‐deficient mouse revealed T‐cell lymphopenia, with increased T‐cell turnover and decreased survival. Egress of mature CD4⁺ thymocytes was reduced with increased migration of these cells to the chemokine CXCL12. However, despite the two‐fold reduction in peripheral naïve T cells, the DOCK8‐deficient mice generated a normal primary CD8⁺ immune response and were able to survive acute influenza virus infection. The limiting effect of DOCK8 was in the normal survival of CD8⁺ memory T cells after infection. These findings help to explain why DOCK8‐deficient patients are susceptible to recurrent infections and provide new insights into how T‐cell memory is sustained.     

Steroid and nonsteroidal anti-inflammatory drugs, cognitive decline, and dementia

The aim of this study was to evaluate the effects of anti-inflammatory intake on cognitive function in 7234 community-dwelling elderly persons. Cognitive performance, clinical diagnosis of dementia, and anti-inflammatory use were evaluated at baseline, and 2, 4, and 7 years later. Multivariate logistic regression analyses were adjusted for sociodemographic, behavioral, physical, mental health variables, and genetic vulnerability (apolipoprotein E ε4). Elderly women taking inhaled corticosteroids were at increased risk for cognitive decline over 7 years in executive functioning (odds ratio, 1.76; 95% confidence interval, 1.14-2.71; p = 0.04); the effect being increased after continuous use (odds ratio, 3.15; 95% confidence interval, 1.29-7.68; p = 0.01) and not found after discontinuation of treatment. In men, no significant associations were observed. Corticosteroid use was not significantly associated with an increase risk of incident dementia over 7 years. Nonsteroidal anti-inflammatory drug use was not significantly associated with either dementia incidence or cognitive decline in both sexes. The association may be related to hypothalamic-pituitary-adrenal corticotropic axis dysfunctioning rather than a direct anti-inflammatory mechanism. Long-term use of inhaled corticosteroids may constitute a form of reversible cognitive disorder in elderly women. Physicians should check this possibility before assuming neurodegenerative changes.     

A defect of the INK4-Cdk4 checkpoint and Myc collaborate in blastoid mantle cell lymphoma-like lymphoma formation in mice

Mantle cell lymphoma (MCL) is a B-cell malignancy characterized by a monoclonal proliferation of lymphocytes with the co-expression of CD5 and CD43, but not of CD23. Typical MCL is associated with overexpression of cyclin D1, and blastoid MCL variants are associated with Myc (alias c-myc) translocations. In this study, we developed a murine model of MCL-like lymphoma by crossing Cdk4(R24C) mice with Myc-3'RR transgenic mice. The Cdk4(R24C) mouse is a knockin strain that expresses a Cdk4 protein that is resistant to inhibition by p16(INK4a) as well as other INK4 family members. Ablation of INK4 control on Cdk4 does not affect lymphomagenesis, B-cell maturation, and functions in Cdk4(R24C) mice. Additionally, B cells were normal in numbers, cell cycle activity, mitogen responsiveness, and Ig synthesis in response to activation. By contrast, breeding Cdk4(R24C) mice with Myc-3'RR transgenic mice prone to develop aggressive Burkitt lymphoma-like lymphoma (CD19(+)IgM(+)IgD(+) cells) leads to the development of clonal blastoid MCL-like lymphoma (CD19(+)IgM(+)CD5(+)CD43(+)CD23(-) cells) in Myc/Cdk4(R24C) mice. Western blot analysis revealed high amounts of Cdk4/cyclin D1 complexes as the main hallmark of these lymphomas. These results indicate that although silent in nonmalignant B cells, a defect in the INK4-Cdk4 checkpoint can participate in lymphomagenesis in conjunction with additional alterations of cell cycle control, a situation that might be reminiscent of the development of human blastoid MCL.