Impaired tumor necrosis factor-α secretion by CD4 T cells during respiratory syncytial virus bronchiolitis associated with recurrent wheeze.

Background: Infants with severe respiratory syncytial virus (RSV) bronchiolitis have an increased risk of recurrent wheezing and asthma. We aimed to evaluate the relationships between regulatory T cell (Treg) percentage and cytokine production of in vitro-stimulated CD4+ T cells during acute bronchiolitis and the development of recurrent wheezing in the first 3 years of life.

Methods: We obtained peripheral blood from 166 infants hospitalized with their first episode of RSV-confirmed bronchiolitis.

Clinical significance of the bronchodilator response in children with severe asthma.

Background: Our objective was to determine those characteristics associated with reversibility of airflow obstruction and response to maximal bronchodilation in children with severe asthma through the Severe Asthma Research Program (SARP).

Methods: We performed a cross-sectional analysis evaluating children ages 6 to 17 years with nonsevere asthma (NSA) and severe asthma (SA). Participants underwent spirometry before and after 180 µg of albuterol to determine reversibility (≥12% increase in FEV ).

Temporal biological variability in dendritic cells and regulatory T cells in peripheral blood of healthy adults.

Background: Studies evaluating circulating dendritic cells (DCs) and natural and induced regulatory T cells (nTregs, iTregs) are often obtained at a single time point and difficult to interpret without understanding their intrinsic day-to-day biologic variability.

Methods: We investigated the day-to-day variability in quantifying DCs, nTregs (FoxP3(+)CD25(+)CD4(+)) and cytokine production by iTregs (granzyme B-GZB, Th1/2 cytokines following CD3 plus CD46 in vitro activation) from peripheral blood mononuclear cells (PBMCs) collected on three consecutive days in healthy adults. Intraclass correlation coefficients (ICCs) were used to evaluate intra-individual variability.

Reactivation of multiple viruses in patients with sepsis.

A current controversy is whether patients with sepsis progress to an immunosuppressed state. We hypothesized that reactivation of latent viruses occurred with prolonged sepsis thereby providing evidence of clinically-relevant immunosuppression and potentially providing a means to serially-monitor patients' immune status. Secondly, if viral loads are markedly elevated, they may contribute to morbidity and mortality.

Cutting edge: A double-mutant knockin of the CD28 YMNM and PYAP motifs reveals a critical role for the YMNM motif in regulation of T cell proliferation and Bcl-xL expression.

CD28 is a critical regulator of T cell function, augmenting proliferation, cytokine secretion, and cell survival. Our previous work using knockin mice expressing point mutations in CD28 demonstrated that the distal proline motif was primarily responsible for much of CD28 function, whereas in marked contrast to prior studies, mutation of the PI3K-binding motif had little discernible effect. In this study, we examined the phenotype of mice in which both motifs are simultaneously mutated.

Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells.

Regulatory T cells (Treg cells) express members of the tumor-necrosis factor (TNF) receptor superfamily (TNFRSF), but the role of those receptors in the thymic development of Treg cells is undefined. We found here that Treg cell progenitors had high expression of the TNFRSF members GITR, OX40 and TNFR2. Expression of those receptors correlated directly with the signal strength of the T cell antigen receptor (TCR) and required the coreceptor CD28 and the kinase TAK1.

A detailed phenotypic analysis of immune cell populations in the bronchoalveolar lavage fluid of atopic asthmatics after segmental allergen challenge.

Background: Atopic asthma is characterized by intermittent exacerbations triggered by exposure to allergen. Exacerbations are characterized by an acute inflammatory reaction in the airways, with recruitment of both innate and adaptive immune cells. These cell populations as well as soluble factors are critical for initiating and controlling the inflammatory processes in allergic asthma.

The changing immune system in sepsis: is individualized immuno-modulatory therapy the answer?

Sepsis remains the leading cause of death in most intensive care units. Advances in understanding the immune response to sepsis provide the opportunity to develop more effective therapies. The immune response in sepsis can be characterized by a cytokine-mediated hyper-inflammatory phase, which most patients survive, and a subsequent immune-suppressive phase.

A randomized controlled trial to evaluate inhibition of T-cell costimulation in allergen-induced airway inflammation.

Rationale: T lymphocytes are important in the pathogenesis of allergic asthma. Costimulation through CD28 is critical for optimal activation of T cells, and inhibition of this pathway with CTLA4Ig has been shown to be effective in preventing airway inflammation and hyperresponsiveness in animal models of asthma. Abatacept, a humanized version of CTLA4Ig, has been approved for treatment of rheumatoid arthritis, providing the opportunity to test whether inhibition of costimulation is an effective strategy to treat people with asthma.

A prospective analysis of lymphocyte phenotype and function over the course of acute sepsis.

Introduction: Severe sepsis is characterized by an initial hyper-inflammatory response that may progress to an immune-suppressed state associated with increased susceptibility to nosocomial infection. Analysis of samples obtained from patients who died of sepsis has identified expression of specific inhibitory receptors expressed on lymphocytes that are associated with cell exhaustion. The objective of this study was to prospectively determine the pattern of expression of these receptors and immune cell function in patients with acute sepsis.

Immunosuppression in patients who die of sepsis and multiple organ failure.

Context: Severe sepsis is typically characterized by initial cytokine-mediated hyperinflammation. Whether this hyperinflammatory phase is followed by immunosuppression is controversial. Animal studies suggest that multiple immune defects occur in sepsis, but data from humans remain conflicting.

An enigmatic tail of CD28 signaling.

CD28 costimulation regulates a wide range of cellular processes, from proliferation and survival to promoting the differentiation of specialized T-cell subsets. Since first being identified over 20 years ago, CD28 has remained a subject of intense study because of its profound consequences on T cell function and its potential for therapeutic manipulation. In this review we highlight the signaling cascades initiated by the major signaling motifs in CD28, focusing on PI-3 kinase-dependent and -independent pathways and how these are linked to specific cellular outcomes.

CTLA4-Ig inhibits allergic airway inflammation by a novel CD28-independent, nitric oxide synthase-dependent mechanism.

The T-cell response to antigen depends upon coordinate signaling between costimulatory and inhibitory receptors. Altered function of either may underlie the pathophysiology of autoimmune and/or chronic inflammatory diseases and manipulation of these pathways is an important emerging area of therapeutics. We report here that the immunosuppressant drug CTLA4-Ig inhibits the effector phase of allergic airway inflammation through a CD28-independent, nitric oxide synthase dependent mechanism.

Targeted knock-in mice expressing mutations of CD28 reveal an essential pathway for costimulation.

Despite extensive study, the role of phosphatidylinositol 3-kinase (PI3-kinase) activation in CD28 function has been highly contentious. To definitively address this question, we generated knock-in mice expressing mutations in two critical domains of the cytoplasmic tail of CD28. Mutation of the proximal tyrosine motif interrupted PI3-kinase binding and prevented CD28-dependent phosphorylation of protein kinase B (PKB)/Akt; however, there was no detectable effect on interleukin-2 (IL-2) secretion, expression of Bcl-X(L), or on T-cell function in vivo.

Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cell-mediated immune responses.

HPK1 is a Ste20-related serine-threonine kinase that inducibly associates with the adaptors SLP-76 and Gads after T cell receptor (TCR) signaling. Here, HPK1 deficiency resulted in enhanced TCR-induced phosphorylation of SLP-76, phospholipase C-gamma1 and the kinase Erk, more-persistent calcium flux, and increased production of cytokines and antigen-specific antibodies. Furthermore, HPK1-deficient mice were more susceptible to experimental autoimmune encephalomyelitis.

Functional interactions of HPK1 with adaptor proteins.

Hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) is a hematopoietic-specific mammalian STE20-like protein serine/threonine kinase, comprised of a STE20-like kinase domain in its N-terminus, four proline-rich motifs, a caspase cleavage site, and a distal C-terminal Citron homology domain. HPK1 is involved in many cellular signaling cascades that include MAPK signaling, antigen receptor signaling, apoptosis, growth factor signaling, and cytokine signaling. HPK1 binds many adaptor proteins including members of the Grb2 family, Nck family, Crk family, SLP-76 family, and actin-binding adaptors like HIP-55.

Protein phosphatase 4 is a positive regulator of hematopoietic progenitor kinase 1.

Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic specific mammalian Ste20-like protein kinase and has been implicated in many cellular signaling pathways including T cell receptor (TCR) signaling. However, little is known about the in vivo regulation of HPK1. We present evidence that HPK1 is positively regulated by protein phosphatase 4 (PP4; also called PPX and PPP4), a serine/threonine phosphatase.