Soluble factors in tolerance and contact sensitivity to 2,4-dinitro-fluorobenzene in mice. IX. A monoclonal T cell suppressor molecule is structurally and serologically related to the alpha/beta T cell receptor

Ts cells from mice tolerized with dinitrobenzene sulfonate produce a DNP-specific, MHC-restricted soluble suppressor factor (SSF) which regulates contact sensitivity to 2,4-dinitro-fluorobenzene. Previous studies have shown that the SSF-producing T cells and the soluble factor have the same hapten/MHC specificity suggesting that SSF may represent a secreted form of the Ts membrane receptor. The relationship between TCR proteins and SSF was investigated by examining the structural and serologic properties of a monoclonal DNP/H-2Kd-specific suppressor molecule produced by a Ts hybridoma. Reduction followed by alkylation abrogated the ability of the 3-10 molecule to inhibit transfer of contact sensitivity to 2,4-dinitro-fluorobenzene, indicating that intact disulfide bonds were a required structural property for suppression. Reduction of the 3-10 molecule followed by affinity chromatography on DNP-coupled Sepharose beads indicated that the 3-10 suppressor molecule is a dimer and that one of its chains binds to cell-free DNP. Serologic properties of the 3-10 molecule were examined by determining the ability of pan-reactive rabbit anti-TCR antibodies and anti-V beta 8 mAb KJ16.133 and F23.1 to adsorb suppressor activity from 3-10 culture supernatant and affinity purified 3-10 ascites material. All three reagents adsorbed the suppressor activity whereas control antibodies had no effect. When 3-10 material was passed through a F23.1-conjugated Sepharose affinity column, suppressor activity was recovered in the column eluate but not in the effluent fraction. When the 3-10 molecule was reduced and separated into its two chains (i.e., DNP-binding and non-DNP-binding chains), it was found that the anti-V beta 8 antibody F23.1-bound to the non-DNP-binding chain of the suppressor molecule. Collectively, these results indicate that the monoclonal 3-10 suppressor molecule is structurally similar to the alpha/beta TCR and suggest that the 3-10 molecule expresses a determinant encoded by the V beta 8 family of TCR genes. These results are consistent with our hypothesis that these suppressor molecules represent a secreted form of the TCR expressed on the surface of the DNP-specific Ts.     

Using heterogeneous data to identify signatures of dengue outbreaks at fine spatio-temporal scales across Brazil

Dengue virus remains a significant public health challenge in Brazil, and seasonal preparation efforts are hindered by variable intra- and interseasonal dynamics. Here, we present a framework for characterizing weekly dengue activity at the Brazilian mesoregion level from 2010–2016 as time series properties that are relevant to forecasting efforts, focusing on outbreak shape, seasonal timing, and pairwise correlations in magnitude and onset. In addition, we use a combination of 18 satellite remote sensing imagery, weather, clinical, mobility, and census data streams and regression methods to identify a parsimonious set of covariates that explain each time series property. The models explained 54% of the variation in outbreak shape, 38% of seasonal onset, 34% of pairwise correlation in outbreak timing, and 11% of pairwise correlation in outbreak magnitude. Regions that have experienced longer periods of drought sensitivity, as captured by the “normalized burn ratio,” experienced less intense outbreaks, while regions with regular fluctuations in relative humidity had less regular seasonal outbreaks. Both the pairwise correlations in outbreak timing and outbreak trend between mesoresgions were best predicted by distance. Our analysis also revealed the presence of distinct geographic clusters where dengue properties tend to be spatially correlated. Forecasting models aimed at predicting the dynamics of dengue activity need to identify the most salient variables capable of contributing to accurate predictions. Our findings show that successful models may need to leverage distinct variables in different locations and be catered to a specific task, such as predicting outbreak magnitude or timing characteristics, to be useful. This advocates in favor of “adaptive models” rather than “one-size-fits-all” models. The results of this study can be applied to improving spatial hierarchical or target-focused forecasting models of dengue activity across Brazil.