CD4 memory T cells divide poorly in response to antigen because of their cytokine profile

Immunological memory is a hallmark of adaptive immunity, and understanding T cell memory will be central to the development of effective cell-mediated vaccines. The characteristics and functions of CD4 memory cells have not been well defined. Here we demonstrate that the increased size of the secondary response is solely a consequence of the increased antigen-specific precursor frequency within the memory pool. Memory cells proliferated less than primary responding cells, even within the same host. By analyzing the entry of primary and memory cells into the cell cycle, we found that the two populations proliferated similarly until day 5; after this time, fewer of the reactivated memory cells proliferated. At this time, fewer of the reactivated memory cells made IL-2 than primary responding cells, but more made IFNγ. Both these factors affected the low proliferation of the memory cells, because either exogenous IL-2 or inhibition of IFNγ increased the proliferation of the memory cells

Dynamics of Relativistic Interacting Gases : from a Kinetic to a Fluid Description

Starting from a microscopic approach, we develop a covariant formalism to describe a set of interacting gases. For that purpose, we model the collision term entering the Boltzmann equation for a class of interactions and then integrate this equation to obtain an effective macroscopic description. This formalism will be useful to study the cosmic microwave background non-perturbatively in inhomogeneous cosmologies. It should also be useful for the study of the dynamics of the early universe and can be applied, if one considers fluids of galaxies, to the study of structure formation.Comment: Latex file, 28 pages, accepted for publication in Class. Quant. Gra

Cd4+ T Cell Subsets during Virus Infection: Protective Capacity Depends on Effector Cytokine Secretion and on Migratory Capability

To analyze the antiviral protective capacities of CD4+ T helper (Th) cell subsets, we used transgenic T cells expressing an I-Ab–restricted T cell receptor specific for an epitope of vesicular stomatitis virus glycoprotein (VSV-G). After polarization into Th1 or Th2 effectors and adoptive transfer into T cell–deficient recipients, protective capacities were assessed after infection with different types of viruses expressing the VSV-G. Both Th1 and Th2 CD4+ T cells could transfer protection against systemic VSV infection, by stimulating the production of neutralizing immunoglobulin G antibodies. However, only Th1 CD4+ T cells were able to mediate protection against infection with recombinant vaccinia virus expressing the VSV-G (Vacc-IND-G). Similarly, only Th1 CD4+ T cells were able to rapidly eradicate Vacc-IND-G from peripheral organs, to mediate delayed-type hypersensitivity responses against VSV-G and to protect against lethal intranasal infection with VSV. Protective capacity correlated with the ability of Th1 CD4+ T cells to rapidly migrate to peripheral inflammatory sites in vivo and to respond to inflammatory chemokines that were induced after virus infection of peripheral tissues. Therefore, the antiviral protective capacity of a given CD4+ T cell is governed by the effector cytokines it produces and by its migratory capability

Chronic viral infections persistently alter marrow stroma and impair hematopoietic stem cell fitness

Chronic viral infections are associated with hematopoietic suppression, bone marrow (BM) failure, and hematopoietic stem cell (HSC) exhaustion. However, how persistent viral challenge and inflammatory responses target BM tissues and perturb hematopoietic competence remains poorly understood. Here, we combine functional analyses with advanced 3D microscopy to demonstrate that chronic infection with lymphocytic choriomeningitis virus leads to (1) long-lasting decimation of the BM stromal network of mesenchymal CXCL12-abundant reticular cells, (2) proinflammatory transcriptional remodeling of remaining components of this key niche subset, and (3) durable functional defects and decreased competitive fitness in HSCs. Mechanistically, BM immunopathology is elicited by virus-specific, activated CD8 T cells, which accumulate in the BM via interferon-dependent mechanisms. Combined antibody-mediated inhibition of type I and II IFN pathways completely preempts degeneration of CARc and protects HSCs from chronic dysfunction. Hence, viral infections and ensuing immune reactions durably impact BM homeostasis by persistently decreasing the competitive fitness of HSCs and disrupting essential stromal-derived, hematopoietic-supporting cues

Swiss Adult Congenital HEart disease Registry (SACHER) - rationale, design and first results.

In 2013, a prospective registry for adults with congenital heart disease (CHD) was established in Switzerland, providing detailed data on disease characteristics and outcomes: Swiss Adult Congenital HEart disease Registry (SACHER). Its aim is to improve the knowledge base of outcomes in adults with CHD. The registry design and baseline patient characteristics are reported. All patients with structural congenital heart defects or hereditary aortopathies, followed-up at dedicated adult CHD clinics, are asked to participate in SACHER. Data of participants are pseudonymised and collected in an electronic, web-based, database (secuTrial®). Collected data include detailed diagnosis, type of repair procedures, previous complications and adverse outcomes during follow-up. From May 2014 to December 2016, 2836 patients (54% male, mean age 34 ± 14 years), with a wide variety of congenital heart lesions, have been enrolled into SACHER. Most prevalent were valve lesions (25%), followed by shunt lesions (22%), cyanotic and other complex congenital heart disease (16%), diseases affecting the right heart, i.e., tetralogy of Fallot or Ebstein anomaly (15%), and diseases of the left ventricular outflow tract (13%); 337 patients (12%) had concomitant congenital syndromes. The majority had undergone previous repair procedures (71%), 47% of those had one or more reinterventions. SACHER collects multicentre data on adults with CHD. Its structure enables prospective data analysis to assess detailed, lesion-specific outcomes with the aim to finally improve long-term outcomes

Predictors of quality of life in young adults with congenital heart disease

Aims: The aim of this study was to identify medical and psychosocial risk factors for impaired health-related quality of life (HRQoL) and poor psychological adjustment (PA) in young adults with congenital heart disease (CHD). Methods and Results: A group of 188 patients (43% females, ages 18-30 years) with various types of CHD and 139 age-matched healthy controls (57% females) completed questionnaires assessing HRQoL, PA, social support, significant life events in the past year, education level, civil status, and employment status. Medical variables were retrieved from the patients' hospital records. Patients reported worse physical HRQoL than controls but similar mental HRQoL and PA. Female CHD patients showed worse physical and mental HRQoL and poorer PA than males. In CHD patients, a lower educational level and lower physical exercise capacity predicted lower physical HRQoL, but complexity of CHD was not related to HRQoL or PA. Less social support was associated with lower mental HRQoL and poorer PA in CHD patients. Conclusion: Young adults with CHD have impaired physical HRQoL but normal mental HRQoL and PA. Lower physical exercise capacity, female sex, less social support and lower educational level predict an unfavorable quality of life and PA. This subgroup of patients should be monitored more closely and provided with special psychosocial care to improve long-term outcome

High prevalence of low affinity peptide–MHC II tetramer–negative effectors during polyclonal CD4+ T cell responses

Two-dimensional analysis reveals that peptide–MHC class II tetramers underestimate the frequency of cytokine-producing antigen-specific CD4+ T cells in polyclonal responses

The Impact of T Cell Intrinsic Antigen Adaptation on Peripheral Immune Tolerance

Overlapping roles have been ascribed for T cell anergy, clonal deletion, and regulation in the maintenance of peripheral immunological tolerance. A measurement of the individual and additive impacts of each of these processes on systemic tolerance is often lacking. In this report we have used adoptive transfer strategies to tease out the unique contribution of T cell intrinsic receptor calibration (adaptation) in the maintenance of tolerance to a systemic self-antigen. Adoptively transferred naïve T cells stably calibrated their responsiveness to a persistent self-antigen in both lymphopenic and T cell–replete hosts. In the former, this state was not accompanied by deletion or suppression, allowing us to examine the unique contribution of adaptation to systemic tolerance. Surprisingly, adapting T cells could chronically help antigen-expressing B cells, leading to polyclonal hypergammaglobulinemia and pathology, in the form of mild arthritis. The helper activity mediated by CD40L and cytokines was evident even if the B cells were introduced after extended adaptation of the T cells. In contrast, in the T cell–replete host, neither arthritis nor autoantibodies were induced. The containment of systemic pathology required host T cell–mediated extrinsic regulatory mechanisms to synergize with the cell intrinsic adaptation process. These extrinsic mechanisms prevented the effector differentiation of the autoreactive T cells and reduced their precursor frequency, in vivo