Clinical impact of Internet-based tools to guide therapeutic decisions for mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a rare cancer with diverse management options. Although clinical practice guidelines have become ubiquitous across medicine, the utility of guidelines for MCL management is limited by provider awareness and the lack of a definitive standard of care. We sought to determine whether expert recommendations, delivered as an online decision support tool, impacted practitioners' therapeutic decisions with MCL. Participants were more likely than the experts to select aggressive regimens for both newly diagnosed and relapsed/refractory MCL. After seeing the expert recommendations, participants revealed that the expert opinion impacted their treatment choices in 103 of 365 clinical scenarios, suggesting that online decision support tools may increase the number of clinicians making treatment decisions for patients with MCL that are concordant with expert consensus recommendations.

Low 2-dimensional CD4 T cell receptor affinity for myelin sets in motion delayed response kinetics.

T cells recognizing self-peptides that mediate autoimmune disease and those that are responsible for efficacious immunity against pathogens may differ in affinity for antigen due to central and peripheral tolerance mechanisms. Here we utilize prototypical self-reactive (myelin) and viral-specific (LCMV) T cells from T cell receptor (TCR) transgenic mice (2D2 and SMARTA, respectively) to explore affinity differences. The T cells responsive to virus possessed >10,000 fold higher 2D affinity as compared to the self-reactive T cells. Despite their dramatically lower affinity for their cognate ligand, 2D2 T cells respond with complete, albeit delayed, activation (proliferation and cytokine production). SMARTA activation occurs rapidly, achieving peak phosphorylation of p38 (1 minute), Erk (30 minutes), and Jun (3 hours) as well as CD69 and CD25 upregulation (3 and 6 hours, respectively), with a corresponding early initiation of proliferation. 2D2 stimulation with MOG results in altered signaling--no phospho-Erk or phospho-p38 accumulation, significantly delayed activation kinetics of Jun (12 hours), and delayed but sustained SHP-1 activity--as well as delayed CD69 and CD25 expression (12-24 hours), and slow initiation of proliferation. This delay was not intrinsic to the 2D2 T cells, as a more potent antigen with >100-fold increased 2D affinity restored rapid response kinetics in line with those identified for the viral antigen. Taken together, these data demonstrate that time can offset low TCR affinity to attain full activation and suggest a mechanism by which low affinity T cells participate in autoimmune disease.

Manipulating antigenic ligand strength to selectively target myelin-reactive CD4+ T cells in EAE.

The development of antigen-specific therapies for the selective tolerization of autoreactive T cells remains the Holy Grail for the treatment of T-cell-mediated autoimmune diseases such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). This quest remains elusive, however, as the numerous antigen-specific strategies targeting myelin-specific T cells over the years have failed to result in clinical success. In this review, we revisit the antigen-based therapies used in the treatment of myelin-specific CD4+ T cells in the context of the functional avidity and the strength of signal of the encephalitogenic CD4+ T cell repertoire. In light of differences in activation thresholds, we propose that autoreactive T cells are not all equal, and therefore tolerance induction strategies must incorporate ligand strength in order to be successful in treating EAE and ultimately the human disease MS.

Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity.

Immune sensing of a microbe occurs via multiple receptors. How signals from different receptors are coordinated to yield a specific immune response is poorly understood. We show that two pathogen recognition receptors, Toll-like receptor 2 (TLR2) and dectin-1, recognizing the same microbial stimulus, stimulate distinct innate and adaptive responses. TLR2 signaling induced splenic dendritic cells (DCs) to express the retinoic acid metabolizing enzyme retinaldehyde dehydrogenase type 2 and interleukin-10 (IL-10) and to metabolize vitamin A and stimulate Foxp3(+) T regulatory cells (T(reg) cells). Retinoic acid acted on DCs to induce suppressor of cytokine signaling-3 expression, which suppressed activation of p38 mitogen-activated protein kinase and proinflammatory cytokines. Consistent with this finding, TLR2 signaling induced T(reg) cells and suppressed IL-23 and T helper type 17 (T(H)17) and T(H)1-mediated autoimmune responses in vivo. In contrast, dectin-1 signaling mostly induced IL-23 and proinflammatory cytokines and augmented T(H)17 and T(H)1-mediated autoimmune responses in vivo. These data define a new mechanism for the systemic induction of retinoic acid and immune suppression against autoimmunity.