CD4(+)CD25(+)FOXP3(+) Regulatory T Cells Suppress Anti-Tumor Immune Responses in Patients with Colorectal Cancer

BACKGROUND: A wealth of evidence obtained using mouse models indicates that CD4(+)CD25(+)FOXP3(+) regulatory T cells (Treg) maintain peripheral tolerance to self-antigens and also inhibit anti-tumor immune responses. To date there is limited information about CD4(+) T cell responses in patients with colorectal cancer (CRC). We set out to measure T cell responses to a tumor-associated antigen and examine whether Treg impinge on those anti-tumor immune responses in CRC patients. METHODOLOGY AND PRINCIPAL FINDINGS: Treg were identified and characterized as CD4(+)CD25(+)FOXP3(+) using flow cytometry. An increased frequency of Treg was demonstrated in both peripheral blood and mesenteric lymph nodes of patients with colorectal cancer (CRC) compared with either healthy controls or patients with inflammatory bowel disease (IBD). Depletion of Treg from peripheral blood mononuclear cells (PBMC) of CRC patients unmasked CD4(+) T cell responses, as observed by IFNγ release, to the tumor associated antigen 5T4, whereas no effect was observed in a healthy age-matched control group. CONCLUSIONS/SIGNIFICANCE: Collectively, these data demonstrate that Treg capable of inhibiting tumor associated antigen-specific immune responses are enriched in patients with CRC. These results support a rationale for manipulating Treg to enhance cancer immunotherapy

Phylodynamic Reconstruction Reveals Norovirus GII.4 Epidemic Expansions and their Molecular Determinants

Noroviruses are the most common cause of viral gastroenteritis. An increase in the number of globally reported norovirus outbreaks was seen the past decade, especially for outbreaks caused by successive genogroup II genotype 4 (GII.4) variants. Whether this observed increase was due to an upswing in the number of infections, or to a surveillance artifact caused by heightened awareness and concomitant improved reporting, remained unclear. Therefore, we set out to study the population structure and changes thereof of GII.4 strains detected through systematic outbreak surveillance since the early 1990s. We collected 1383 partial polymerase and 194 full capsid GII.4 sequences. A Bayesian MCMC coalescent analysis revealed an increase in the number of GII.4 infections during the last decade. The GII.4 strains included in our analyses evolved at a rate of 4.3–9.0×10−3 mutations per site per year, and share a most recent common ancestor in the early 1980s. Determinants of adaptation in the capsid protein were studied using different maximum likelihood approaches to identify sites subject to diversifying or directional selection and sites that co-evolved. While a number of the computationally determined adaptively evolving sites were on the surface of the capsid and possible subject to immune selection, we also detected sites that were subject to constrained or compensatory evolution due to secondary RNA structures, relevant in virus-replication. We highlight codons that may prove useful in identifying emerging novel variants, and, using these, indicate that the novel 2008 variant is more likely to cause a future epidemic than the 2007 variant. While norovirus infections are generally mild and self-limiting, more severe outcomes of infection frequently occur in elderly and immunocompromized people, and no treatment is available. The observed pattern of continually emerging novel variants of GII.4, causing elevated numbers of infections, is therefore a cause for concern

Protective Efficacy of Serially Up-Ranked Subdominant CD8+ T Cell Epitopes against Virus Challenges

Immunodominance in T cell responses to complex antigens like viruses is still incompletely understood. Some data indicate that the dominant responses to viruses are not necessarily the most protective, while other data imply that dominant responses are the most important. The issue is of considerable importance to the rational design of vaccines, particularly against variable escaping viruses like human immunodeficiency virus type 1 and hepatitis C virus. Here, we showed that sequential inactivation of dominant epitopes up-ranks the remaining subdominant determinants. Importantly, we demonstrated that subdominant epitopes can induce robust responses and protect against whole viruses if they are allowed at least once in the vaccination regimen to locally or temporally dominate T cell induction. Therefore, refocusing T cell immune responses away from highly variable determinants recognized during natural virus infection towards subdominant, but conserved regions is possible and merits evaluation in humans

T-cell responses to human papillomavirus type 16 among women with different grades of cervical neoplasia

Infection with high-risk genital human papillomavirus (HPV) types is a major risk factor for the development of cervical intraepithelial neoplasia (CIN) and invasive cervical carcinoma. The design of effective immunotherapies requires a greater understanding of how HPV-specific T-cell responses are involved in disease clearance and/or progression. Here, we have investigated T-cell responses to five HPV16 proteins (E6, E7, E4, L1 and L2) in women with CIN or cervical carcinoma directly ex vivo. T-cell responses were observed in the majority (78%) of samples. The frequency of CD4+ responders was far lower among those with progressive disease, indicating that the CD4+ T-cell response might be important in HPV clearance. CD8+ reactivity to E6 peptides was dominant across all disease grades, inferring that E6-specific CD8+ T cells are not vitally involved in disease clearance. T-cell responses were demonstrated in the majority (80%) of cervical cancer patients, but are obviously ineffective. Our study reveals significant differences in HPV16 immunity during progressive CIN. We conclude that the HPV-specific CD4+ T-cell response should be an important consideration in immunotherapy design, which should aim to target preinvasive disease

Teaching: Natural or Cultural?

In this chapter I argue that teaching, as we now understand the term, is historically and cross-culturally very rare. It appears to be unnecessary to transmit culture or to socialize children. Children are, on the other hand, primed by evolution to be avid observers, imitators, players and helpers—roles that reveal the profoundly autonomous and self-directed nature of culture acquisition (Lancy in press a). And yet, teaching is ubiquitous throughout the modern world—at least among the middle to upper class segment of the population. This ubiquity has led numerous scholars to argue for the universality and uniqueness of teaching as a characteristically human behavior. The theme of this chapter is that this proposition is unsustainable. Teaching is largely a result of recent cultural changes and the emergence of modern economies, not evolution

25th Annual Computational Neuroscience Meeting: CNS-2016

Abstracts of the 25th Annual Computational Neuroscience Meeting: CNS-2016 Seogwipo City, Jeju-do, South Korea. 2–7 July 201

Last Glacial Inception as a function of initial and surface conditions

We investigate the sensitivity of simulations of the last glacial inception (LGI) with respect to initial (size of the Greenland ice sheet) and surface (state of ocean/vegetation) conditions and two different CO2 reconstructions. Utilizing the CLIMBER-2 Earth system model, we obtain the following results: (a) ice-sheet expansion in North America at the end of the Eemian can be reduced or even completely suppressed when pre-industrial or Eemian ocean/vegetation is prescribed. (b) A warmer surrounding ocean and, in particular, a large Laurentide ice sheet reduce the size of the Greenland ice sheet before and during the LGI. (c) A changing ocean contributes much stronger to the expansion of the Laurentide ice sheet when we apply the CO2 reconstruction according to Barnola et al. (Nature 329:408-414, 1987) instead of Petit et al. (Nature 399:429-436, 1999). (d) In the fully coupled model, the CO2 reconstruction used has only a small impact on the simulated ice sheets but it does impact the course of the climatic variables. (e) For the Greenland ice sheet, two equilibrium states exist under the insolation and CO2 forcing at 128,000 years before present (128 kyear BP); the one with an ice sheet reduced by about one quarter as compared to its simulated pre-industrial size and the other with nearly no inland ice in Greenland. (f) Even the extreme assumption of no ice sheet in Greenland at the beginning of our transient simulations does not alter the simulated expansion of northern hemispheric ice sheets at the LGI

Transient simulation of the last glacial inception. Part II: Sensitivity and feedback analysis

The sensitivity of the last glacial-inception (around 115 kyr BP, 115,000 years before present) to different feedback mechanisms has been analysed by using the Earth system model of intermediate complexity CLIMBER-2. CLIMBER-2 includes dynamic modules of the atmosphere, ocean, terrestrial biosphere and inland ice, the last of which was added recently by utilising the three-dimensonal polythermal ice-sheet model SICOPOLIS. We performed a set of transient experiments starting at the middle of the Eemiam interglacial and ran the model for 26,000 years with time-dependent orbital forcing and observed changes in atmospheric CO2 concentration (CO2 forcing). The role of vegetation and ocean feedback, CO2 forcing, mineral dust, thermohaline circulation and orbital insolation were closely investigated. In our model, glacial inception, as a bifurcation in the climate system, appears in nearly all sensitivity runs including a run with constant atmospheric CO2 concentration of 280 ppmv, a typical interglacial value, and simulations with prescribed present-day sea-surface temperatures or vegetation cover—although the rate of the growth of ice-sheets growth is smaller than in the case of the fully interactive model. Only if we run the fully interactive model with constant present-day insolation and apply present-day CO2 forcing does no glacial inception appear at all. This implies that, within our model, the orbital forcing alone is sufficient to trigger the interglacial–glacial transition, while vegetation, ocean and atmospheric CO2 concentration only provide additional, although important, positive feedbacks. In addition, we found that possible reorganisations of the thermohaline circulation influence the distribution of inland ic