Rapid development of Th2 activity during T cell priming

The paradigm of T helper-1 (Th-1) and Th-2 cells developing from non-committed naïve precursors is firmly established. Th1 cells are characterized by IFN production and, in mice, the selective switching to IgG2a. Conversely IL-4 production and selective switching to IgG1 and IgE characterize Th2 cells. Analysis of Th2 induction in vitro indicates that this polarization develops gradually in T cells activated by anti-CD3 in the presence of IL-4; conversely anti-CD3 and IFN induce Th1 cells. In this report, we explore evidence that indicates that the T helper cell polarization in vivo cannot solely be explained by the cytokine environment. This is provided by studying the early acquisition of Th1 and Th2 activities during responses to a mixture of Th1 and Th2-inducing antigens. It is shown that these divergent forms of T cell help can rapidly develop in cells within a single lymph node. It is argued that early polarization to show Th-1 or Th-2 behavior can be induced by signals delivered during cognate interaction between virgin T cells and dendritic cells, in the absence of type 1 or type 2 cytokines. This contrasts with the critical role of the cytokines in reinforcing the Th-phenotype and selectively expanding T helper clones

Deriving a germinal center lymphocyte migration model from two-photon data

Recently, two-photon imaging has allowed intravital tracking of lymphocyte migration and cellular interactions during germinal center (GC) reactions. The implications of two-photon measurements obtained by several investigators are currently the subject of controversy. With the help of two mathematical approaches, we reanalyze these data. It is shown that the measured lymphocyte migration frequency between the dark and the light zone is quantitatively explained by persistent random walk of lymphocytes. The cell motility data imply a fast intermixture of cells within the whole GC in approximately 3 h, and this does not allow for maintenance of dark and light zones. The model predicts that chemotaxis is active in GCs to maintain GC zoning and demonstrates that chemotaxis is consistent with two-photon lymphocyte motility data. However, the model also predicts that the chemokine sensitivity is quickly down-regulated. On the basis of these findings, we formulate a novel GC lymphocyte migration model and propose its verification by new two-photon experiments that combine the measurement of B cell migration with that of specific chemokine receptor expression levels. In addition, we discuss some statistical limitations for the interpretation of two-photon cell motility measurements in general

Deriving a germinal center lymphocyte migration model from two-photon data

Recently, two-photon imaging has allowed intravital tracking of lymphocyte migration and cellular interactions during germinal center (GC) reactions. The implications of two-photon measurements obtained by several investigators are currently the subject of controversy. With the help of two mathematical approaches, we reanalyze these data. It is shown that the measured lymphocyte migration frequency between the dark and the light zone is quantitatively explained by persistent random walk of lymphocytes. The cell motility data imply a fast intermixture of cells within the whole GC in approximately 3 h, and this does not allow for maintenance of dark and light zones. The model predicts that chemotaxis is active in GCs to maintain GC zoning and demonstrates that chemotaxis is consistent with two-photon lymphocyte motility data. However, the model also predicts that the chemokine sensitivity is quickly down-regulated. On the basis of these findings, we formulate a novel GC lymphocyte migration model and propose its verification by new two-photon experiments that combine the measurement of B cell migration with that of specific chemokine receptor expression levels. In addition, we discuss some statistical limitations for the interpretation of two-photon cell motility measurements in general

Morning vaccination enhances antibody response over afternoon vaccination: A cluster-randomised trial

Objectives Older adults are less able to produce a protective antibody response to vaccinations. One factor that contributes to this is immune ageing. Here we examined whether diurnal variations in immune responses might extend to the antibody response to vaccination. Design We utilised a cluster-randomised trial design. Setting 24 General Practices (GPs) across the West Midlands, UK who were assigned to morning (9–11 am; 15 surgeries) or afternoon (3–5 pm; 9 surgeries) vaccination times for the annual UK influenza vaccination programme. Participants 276 adults (aged 65+ years and without a current infection or immune disorder or taking immunosuppressant medication). Interventions Participants were vaccinated in the morning or afternoon between 2011 and 2013. Main outcome measures The primary outcome was the change in antibody titres to the three vaccine influenza strains from pre-vaccination to one month post-vaccination. Secondary outcomes of serum cytokines and steroid hormone concentrations were analysed at baseline to identify relationships with antibody responses. Results The increase in antibody levels due to vaccination differed between morning and afternoon administration; mean difference (95% CI) for H1N1 A-strain, 293.3 (30.97–555.66) p = .03, B-strain, 15.89 (3.42–28.36) p = .01, but not H3N2 A-strain, 47.0 (−52.43 to 146.46) p = .35; those vaccinated in the morning had a greater antibody response. Cytokines and steroid hormones were not related to antibody responses. No adverse events were reported. Conclusions This simple manipulation in the timing of vaccine administration to favour morning vaccination may be beneficial for the influenza antibody response in older adults, with potential implications for vaccination strategies generally

Low-level Hypermutation in T Cell–independent Germinal Centers Compared with High Mutation Rates Associated with T Cell–dependent Germinal Centers

Exceptionally germinal center formation can be induced without T cell help by polysaccharide-based antigens, but these germinal centers involute by massive B cell apoptosis at the time centrocyte selection starts. This study investigates whether B cells in germinal centers induced by the T cell–independent antigen (4-hydroxy-3-nitrophenyl)acetyl (NP) conjugated to Ficoll undergo hypermutation in their immunoglobulin V region genes. Positive controls are provided by comparing germinal centers at the same stage of development in carrier-primed mice immunized with a T cell–dependent antigen: NP protein conjugate. False positive results from background germinal centers and false negatives from non-B cells in germinal centers were avoided by transferring B cells with a transgenic B cell receptor into congenic controls not carrying the transgene. By 4 d after immunization, hypermutation was well advanced in the T cell–dependent germinal centers. By contrast, the mutation rate for T cell–independent germinal centers was low, but significantly higher than in NP-specific B cells from nonimmunized transgenic mice. Interestingly, a similar rate of mutation was seen in extrafollicular plasma cells at this stage. It is concluded that efficient activation of hypermutation depends on interaction with T cells, but some hypermutation may be induced without such signals, even outside germinal centers