Vdelta2+ T cells, the major circulating T-cell receptor-gammadelta-positive (TCR-gammadelta+) T-cell subset in healthy adults, are involved in immunity against many microbial pathogens including Mycobacterium tuberculosis. Vdelta2+ T cells recognize small phosphorylated metabolites (phosphoantigens), expand in response to whole M. tuberculosis bacilli, and complement the protective functions of CD4+ T cells. CD4+ CD25(high) Foxp3+ T cells (Tregs) comprise 5-10% of circulating T cells and are increased in patients with active tuberculosis (TB). We investigated whether, in addition to their known role in suppressing TCR-alphabeta+ lymphocytes, Tregs suppress Vdelta2+ T-cell function. We found that depletion of Tregs from peripheral blood mononuclear cells increased Vdelta2+ T-cell expansion in response to M. tuberculosis (H37Ra) in tuberculin-skin-test-positive donors. We developed a suppression assay with fluorescence-activated cell sorting-purified Tregs and Vdelta2+ T cells by coincubating the two cell types at a 1 : 1 ratio. The Tregs partially suppressed interferon-gamma secretion by Vdelta2+ T cells in response to anti-CD3 monoclonal antibody plus interleukin-2 (IL-2). In addition, Tregs downregulated the Vdelta2+ T-cell interferon-gamma responses induced by phosphoantigen (BrHPP) and IL-2. Under the latter conditions there was no TCR stimulus for Tregs and therefore IL-2 probably triggered suppressor activity. Addition of purified protein derivative (PPD) increased the suppression of Vdelta2+ T cells, suggesting that PPD activated antigen-specific Tregs. Our study provides evidence that Tregs suppress both anti-CD3 and antigen-driven Vdelta2+ T-cell activation. Antigen-specific Tregs may therefore contribute to the Vdelta2+ T-cell functional deficiencies observed in TB.
Thirty patients were skin tested by Multi-Test and Morrow Brown needle using antigens, histamine, glycerosaline, and blank controls to examine reproducibility and influence of positive reactions on adjacent negative controls. There was no evidence that histamine or strongly positive antigen reactions affected adjacent negative controls. Multi-Test was more reproducible, and preferred by patients over Morrow Brown.
presenting his work to the UCSF medical school.Slides include midwives, alternative birthing positions and environments, the labor pools and unplanned underwater births.
Background. Human immunodeficiency virus (HIV)–tuberculosis coinfection is associated with heightened immune activation, viral replication, and T cell dysfunction. We compared changes in T cell activation and function between patients receiving concurrent treatment for HIV-tuberculosis coinfection and those receiving treatment for tuberculosis alone.
Abstract The Phenome-Wide Association Study (PheWAS) is increasingly used to broadly screen for potential treatment effects, e.g., IL6R variant as a proxy for IL6R antagonists. This approach offers an opportunity to address the limited power in clinical trials to study differential treatment effects across patient subgroups. However, limited methods exist to efficiently test for differences across subgroups in the thousands of multiple comparisons generated as part of a PheWAS. In this study, we developed an approach that maximizes the power to test for heterogeneous genotype–phenotype associations and applied this approach to an IL6R PheWAS among individuals of African (AFR) and European (EUR) ancestries. We identified 29 traits with differences in IL6R variant-phenotype associations, including a lower risk of type 2 diabetes in AFR (OR 0.96) vs EUR (OR 1.0, p-value for heterogeneity = 8.5 × 10 –3 ), and higher white blood cell count (p-value for heterogeneity = 8.5 × 10 –131 ). These data suggest a more salutary effect of IL6R blockade for T2D among individuals of AFR vs EUR ancestry and provide data to inform ongoing clinical trials targeting IL6 for an expanding number of conditions. Moreover, the method to test for heterogeneity of associations can be applied broadly to other large-scale genotype–phenotype screens in diverse populations.
Roth, Jeffrey; Resnick, Michael B.; Ariet, Mario; Carter, Randy L.; Eitzman, Donald V.; Curran, John S.; Cupoli, J. Michael; Mahan, Charles S.; Bucciarelli, Richard L. Author Information
