Shirin Kalyan

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

The elusive task of defining the character of γδ T cells has been an evolving process for immunologists since stumbling upon their existence during the molecular characterization of the α and β T cell receptor genes of their better understood brethren. Defying the categorical rules used to distinctly characterize lymphocytes as either innate or adaptive in nature, γδ T cells inhabit a hybrid world of their own. At opposing ends of the simplified spectrum of modes of antigen recognition used by lymphocytes, natural killer and αβ T cells are particularly well equipped to respond to the ‘missing self’ and the ‘dangerous non-self’, respectively. However, between these two reductive extremes, we are chronically faced with the challenge of making peace with the ‘safe non-self’ and dealing with the inevitable ‘distressed self’, and it is within this more complex realm γδ T cells excel thanks to their highly empathetic nature. This review gives an overview of the latest insights revealing the unfolding story of human γδ T cells, providing a biographical sketch of these unique lymphocytes in an attempt to capture the essence of their fundamental nature and events that influence their life trajectory. What hangs in their balance is their nuanced ability to differentiate the friends from the foe and the pathological from the benign to help us adapt swiftly and efficiently to lifes many stresses.

Temporal Sequence and Kinetics of Proinflammatory and Anti-Inflammatory Cytokine Secretion Induced by Toxic Shock Syndrome Toxin 1 in Human Peripheral Blood Mononuclear Cells

ABSTRACT The staphylococcal superantigen toxic shock syndrome toxin 1 (TSST-1) induces massive cytokine production, which is believed to be the key factor in the pathogenesis of TSS. The temporal sequence and kinetics of both proinflammatory and anti-inflammatory cytokines induced by TSST-1 in human peripheral blood mononuclear cells were investigated. A panel of loss-of-function single-amino-acid-substitution mutants of TSST-1, previously demonstrated to be defective in either major histocompatibility complex (MHC) class II binding (G31R) or T-cell receptor (TCR) interaction (H135A, S14N), was studied in parallel to further elucidate the mechanisms of cytokine secretion. Wild-type recombinant (WT r) TSST-1 induced a biphasic pattern of cytokine secretion: an early phase with rapid release of proinflammatory cytokines (especially gamma interferon, interleukin-2 [IL-2], and tumor necrosis factor alpha [TNF-α]) within 3 to 4 h poststimulation, and a later phase with more gradual production of both proinflammatory (IL-1β, IL-12, and TNF-β) and anti-inflammatory (IL-6, IL-10) cytokines within 16 to 72 h poststimulation. G31R, which is defective in MHC class II binding, induced a cytokine profile similar to that of WT rTSST-1, except that secretion of the early-phase proinflammatory cytokines was delayed and production of IL-1β and IL-12 was markedly reduced. In contrast, mutant toxins defective in TCR interaction either demonstrated complete absence of any cytokine secretion during the entire observation period (H135A) or resulted in complete abolishment of IL-2 and other early-phase proinflammatory cytokines, while secretion of IL-10 appeared unaffected (S14N). Neither WT rTSST-1 nor the mutant toxins induced IL-4 or transforming growth factor β. Our data indicate that effective TCR interaction is critical for the induction of the early-phase proinflammatory cytokine response, thus underscoring the importance of T-cell signaling in TSS.

Human Vδ2 versus non-Vδ2 γδ T cells in antitumor immunity.

The Vδ2 and non-Vδ2 (mainly Vδ1) subsets of human γδ T cells have distinct homing patterns and recognize different types of ligands, yet both exert potent antitumor effects. While the T-cell receptor of Vδ2 T cells primarily recognizes tumor cell-derived pyrophosphates, non-Vδ2 γδ T cells preferentially recognize stress-associated surface antigens. Here, we discuss the pros and cons of Vδ2 versus non-Vδ2 γδ T cells as tools for future immunotherapeutic interventions against cancer.

Evaluation of methods and costs associated with recruiting healthy women volunteers to a study of ovulation.

OBJECTIVE We address the crucial and challenging task of anticipating the resources needed to recruit eligible participants for research. We provide our analysis of various recruitment strategies and their cost-effectiveness in our experience in enrolling 610 women for an observational study on ovulation. METHODS We assess the cost-effectiveness and success of multiple recruitment strategies we employed and provide the estimated cost of labor and materials for each. At enrollment, all participants were asked an open-ended question about how they learned about the study. No financial compensation was provided, but participants received personal hormonal analysis results on completion. RESULTS Of the 610 enrolled women, 552 provided information on how they learned about the study. The total cost of recruitment was

Human Peripheral γδ T Cells Potentiate the Early Proinflammatory Cytokine Response to Staphylococcal Toxic Shock Syndrome Toxin-1

7645.11, which includes 183 staff hours. The average recruitment cost per participant was

Cardiovascular and Metabolic Effects of Medroxyprogesterone Acetate versus Conjugated Equine Estrogen After Premenopausal Hysterectomy with Bilateral Ovariectomy

12.53 (ranging from

Progesterone therapy increases free thyroxine levels--data from a randomized placebo-controlled 12-week hot flush trial.

0 to

Attenuating immune pathology using a microbial-based intervention in a mouse model of cigarette smoke-induced lung inflammation

118.63). The two methods with the lowest total costs resulted in enrollment of 48% of the recruitment goal using only 0.3% of the budget. In contrast, the two methods with the highest total costs produced 13% of the participants needed but consumed over 72% of the budget. CONCLUSIONS Low-cost methods are a viable, practical source for attracting healthy women for observational research. Investigators are encouraged to track sources of recruitment and analyze their data at regular intervals during the recruitment phase. Sharing comprehensive recruitment data will assist other researchers to better estimate the resources needed to meet their enrollment goal, leading to more efficient use of time and funding.

A novel microbe-based treatment that attenuates the inflammatory profile in a mouse model of allergic airway disease

Toxic shock syndrome toxin (TSST)-1 is a superantigen known to profoundly induce proinflammatory cytokines by activation of V beta -specific alpha beta T cells, but its effect on gamma delta T cells, which normally constitute 1%-5% of peripheral blood mononuclear cells (PBMCs), is unclear. Here, we demonstrate that TSST-1 induced significantly higher levels of interferon (IFN)- gamma, tumor necrosis factor (TNF)- alpha, and interleukin (IL)-2, and a lower level of IL-10 in human PBMCs when the gamma delta subpopulation has been primed by isopentylpyrophosphate, compared with that in control PBMCs. Furthermore, depletion of the gamma delta subpopulation completely abrogated this effect. Thus, peripheral gamma delta T cells markedly modulate both the proinflammatory and anti-inflammatory cytokine responses of TSST-1.

Nitrogen-Bisphosphonate Therapy Is Linked to Compromised Coenzyme Q10 and Vitamin E Status in Postmenopausal Women

Study Objective. To compare the cardiovascular and metabolic effects of medroxyprogesterone acetate (MPA) with those of conjugated equine estrogen (CEE) as single‐hormone therapies in women who underwent hysterectomy with bilateral ovariectomy.