T cells expressing antigen-specific T-cell receptors (TCRs) can mediate effective tumor regression, but they often also are accompanied by autoimmune responses. To determine the TCR affinity threshold defining the optimal balance between effective antitumor activity and autoimmunity in vivo , we used a unique self-antigen system comprising seven human melanoma gp100(209–217)-specific TCRs spanning physiological affinities (1–100 μM). We found that in vitro and in vivo T-cell responses are determined by TCR affinity, except in one case that was compensated by substantial CD8 involvement. Strikingly, we found that T-cell antitumor activity and autoimmunity are closely coupled but plateau at a defined TCR affinity of 10 µM, likely due to diminished contribution of TCR affinity to avidity above the threshold. Together, these results suggest that a relatively low-affinity threshold is necessary for the immune system to avoid self-damage, given the close relationship between antitumor activity and autoimmunity. The low threshold, in turn, indicates that adoptive T-cell therapy treatment strategies using in vitro-generated high-affinity TCRs do not necessarily improve efficacy.

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Jackson, B. V., Boyer, J. A., Hick, P. P., Buffington, A., Bisi, M. M., & Crider, D. H. (2007). Analysis of Solar Wind Events Using Interplanetary Scintillation Remote Sensing 3D Reconstructions and Their Comparison at Mars. Solar Physics, 241 (2), 385-396Interplanetary Scintillation (IPS) allows observation of the inner heliospheric response to corotating solar structures and coronal mass ejections (CMEs) in scintillation level and velocity. With colleagues at STELab, Nagoya University, Japan, we have developed near-real-time access of STELab IPS data for use in space-weather forecasting. We use a 3D reconstruction technique that produces perspective views from solar corotating plasma and outward-flowing solar wind as observed from Earth by iteratively fitting a kinematic solar wind model to IPS observations. This 3D modeling technique permits reconstruction of the density and velocity structure of CMEs and other interplanetary transients at a relatively coarse resolution: a solar rotational cadence and 10? latitudinal and longitudinal resolution for the corotational model and a one-day cadence and 20? latitudinal and longitudinal heliographic resolution for the time-dependent model. This technique is used to determine solar-wind pressure (?ram? pressure) at Mars. Results are compared with ram-pressure observations derived from Mars Global Surveyor magnetometer data (Crider et al. 2003, J. Geophys. Res. 108(A12), 1461) for the years 1999 through 2004. We identified 47 independent in situ pressure-pulse events above 3.5 nPa in the Mars Global Surveyor data in this time period where sufficient IPS data were available. We detail the large pressure pulse observed at Mars in association with a CME that erupted from the Sun on 27 May 2003, which was a halo CME as viewed from Earth. We also detail the response of a series of West-limb CME events and compare their response observed at Mars about 160? west of the Sun?-?Earth line by the Mars Global Surveyor with the response derived from the IPS 3D reconstructions.Peer reviewe

The endocrine pancreas is one of the most inaccessible organs of the human body. Its autoimmune attack leads to type 1 diabetes (T1D) in a genetically susceptible population and a lifelong need for exogenous insulin replacement. Monitoring disease progression by sampling peripheral blood would provide key insights into T1D immune-mediated mechanisms and potentially change preclinical diagnosis and the evaluation of therapeutic interventions. This effort has been limited to the measurement of circulating anti-islet antibodies, which despite a recognized diagnostic value, remain poorly predictive at the individual level for a fundamentally CD4 T cell–dependent disease. Here, peptide–major histocompatibility complex tetramers were used to profile blood anti-insulin CD4 T cells in mice and humans. While percentages of these were not directly informative, the state of activation of anti-insulin T cells measured by RNA and protein profiling was able to distinguish the absence of autoimmunity versus disease progression. Activated anti-insulin CD4 T cell were detected not only at time of diagnosis but also in patients with established disease and in some at-risk individuals. These results support the concept that antigen-specific CD4 T cells might be used to monitor autoimmunity in real time. This advance can inform our approach to T1D diagnosis and therapeutic interventions in the preclinical phase of anti-islet autoimmunity.

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