Induction of CD4 T cell memory by local cellular collectivity.

Cell differentiation is directed by signals driving progenitors into specialized cell types. This process can involve collective decision-making, when differentiating cells determine their lineage choice by interacting with each other. We used live-cell imaging in microwell arrays to study collective processes affecting differentiation of naïve CD4+ T cells into memory precursors. We found that differentiation of precursor memory T cells sharply increases above a threshold number of locally interacting cells. These homotypic interactions involve the cytokines interleukin-2 (IL-2) and IL-6, which affect memory differentiation orthogonal to their effect on proliferation and survival. Mathematical modeling suggests that the differentiation rate is continuously modulated by the instantaneous number of locally interacting cells. This cellular collectivity can prioritize allocation of immune memory to stronger responses.

Diverse continuum of CD4+ T-cell states is determined by hierarchical additive integration of cytokine signals.

During cell differentiation, progenitor cells integrate signals from their environment that guide their development into specialized phenotypes. The ways by which cells respond to complex signal combinations remain difficult to analyze and model. To gain additional insight into signal integration, we systematically mapped the response of CD4+ T cells to a large number of input cytokine combinations that drive their differentiation. We find that, in response to varied input combinations, cells differentiate into a continuum of cell fates as opposed to a limited number of discrete phenotypes. Input cytokines hierarchically influence the cell population, with TGFß being most dominant followed by IL-6 and IL-4. Mathematical modeling explains these results using additive signal integration within hierarchical groups of input cytokine combinations and correctly predicts cell population response to new input conditions. These findings suggest that complex cellular responses can be effectively described using a segmented linear approach, providing a framework for prediction of cellular responses to new cytokine combinations and doses, with implications to fine-tuned immunotherapies.

Pemphigus vulgaris is characterized by low IgG reactivities to specific self-antigens along with high IgG reactivity to desmoglein 3.

Pemphigus vulgaris (PV) is an autoimmune skin disease, which has been characterized by IgG autoantibodies to desmoglein 3. Here we studied the antibody signatures of PV patients compared with healthy subjects and with patients with two other autoimmune diseases with skin manifestations (systemic lupus erythematosus and scleroderma), using an antigen microarray and informatics analysis. We now report a previously unobserved phenomenon--patients with PV, compared with the healthy subjects and the two other diseases, show a significant decrease in IgG autoantibodies to a specific set of self-antigens. This novel finding demonstrates that an autoimmune disease may be associated with a loss of specific, healthy IgG autoantibodies and not only with a gain of specific, pathogenic IgG autoantibodies.

Do all creatures possess an acquired immune system of some sort?

Recent findings have provided evidence for the existence of non-vertebrate acquired immunity. We survey these findings and propose that all living organisms must express both innate and acquired immunity. This is opposed to the paradigm that only vertebrates manifest the two forms of immune mechanism; other species are thought to use innate immunity alone. We suggest new definitions of innate and acquired immunity, based on whether immune recognition molecules are encoded in the inherited genome or are generated through somatic processes. We reason that both forms of immunity are similarly ancient, and have co-evolved in response to lifestyle, cost-benefit tradeoffs and symbiosis versus parasitism. However, different species have evolved different immune solutions that are not necessarily genetically related, but serve a similar general function - allowing individuals to learn from their own immune experience; survival of species is contingent on the acquired immune experience of its individuals.

Mapping differentiation under mixed culture conditions reveals a tunable continuum of T cell fates.

Cell differentiation is typically directed by external signals that drive opposing regulatory pathways. Studying differentiation under polarizing conditions, with only one input signal provided, is limited in its ability to resolve the logic of interactions between opposing pathways. Dissection of this logic can be facilitated by mapping the system's response to mixtures of input signals, which are expected to occur in vivo, where cells are simultaneously exposed to various signals with potentially opposing effects. Here, we systematically map the response of naïve T cells to mixtures of signals driving differentiation into the Th1 and Th2 lineages. We characterize cell state at the single cell level by measuring levels of the two lineage-specific transcription factors (T-bet and GATA3) and two lineage characteristic cytokines (IFN-γ and IL-4) that are driven by these transcription regulators. We find a continuum of mixed phenotypes in which individual cells co-express the two lineage-specific master regulators at levels that gradually depend on levels of the two input signals. Using mathematical modeling we show that such tunable mixed phenotype arises if autoregulatory positive feedback loops in the gene network regulating this process are gradual and dominant over cross-pathway inhibition. We also find that expression of the lineage-specific cytokines follows two independent stochastic processes that are biased by expression levels of the master regulators. Thus, cytokine expression is highly heterogeneous under mixed conditions, with subpopulations of cells expressing only IFN-γ, only IL-4, both cytokines, or neither. The fraction of cells in each of these subpopulations changes gradually with input conditions, reproducing the continuous internal state at the cell population level. These results suggest a differentiation scheme in which cells reflect uncertainty through a continuously tuneable mixed phenotype combined with a biased stochastic decision rather than a binary phenotype with a deterministic decision.

The impact of stratifying initial dose of corticosteroids by severity of pemphigus vulgaris on long-term disease severity.

BACKGROUND: Pemphigus vulgaris (PV) is a life-threatening disease affecting skin and mucous membranes. The "epitope spreading" theory posits that uncontrolled PV can gradually worsen because of exposure of cellular antigens to the immune system. To this end, high-dose systemic corticosteroids have been advocated as first-line treatment for patients with PV to achieve disease control. OBJECTIVE: To determine whether the initial dose of prednisone stratified by disease severity affects long-term disease severity. METHODS: A retrospective study was conducted on 58 patients with PV with at least five years of follow-up from diagnosis. Patients were categorized into three groups according to the initial dose of prednisone treatment. Parameters analyzed included age, gender, disease severity at baseline and follow-up, hospitalizations, prednisone doses and adjuvant therapy at follow-up, and remission rate. RESULTS: Ten patients received initial low-dose prednisone or were treated initially without systemic CS, 19 patients received intermediate-dose prednisone, and 29 received high-dose prednisone. Disease severity at presentation correlated directly with initial prednisone doses. The duration of the first hospitalization and number of hospitalization days during the five-year follow-up period were significantly lower in the group treated with initial low-dose prednisone and similar for the groups treated with intermediate and high doses. CONCLUSIONS: Disease severity of PV at presentation is a good predictor of the clinical course. Stratifying initial prednisone dose according to PV disease severity at presentation is appropriate.