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Feedback regulation of proliferation vs. differentiation rates explains the dependence of CD4 T-cell expansion on precursor number.

ABSTRACT: The mechanisms regulating clonal expansion and contraction of T cells in response to immunization remain to be identified. A recent study established that there was a log-linear relation between CD4 T-cell precursor number (PN) and factor of expansion (FE), with a slope of ?-0.5 over a range of 3-30,000 precursors per mouse. The results suggested inhibition of precursor expansion either by competition for specific antigen-presenting cells or by the action of other antigen-specific cells in the same microenvironment as the most likely explanation. Several molecular mechanisms potentially accounting for such inhibition were examined and rejected. Here we adopt a previously proposed concept, "feedback-regulated balance of growth and differentiation," and show that it can explain the observed findings. We assume that the most differentiated effectors (or memory cells) limit the growth of less differentiated effectors, locally, by increasing the rate of differentiation of the latter cells in a dose-dependent manner. Consequently, expansion is blocked and reversed after a delay that depends on initial PN, accounting for the dependence of the peak of the response on that number. We present a parsimonious mathematical model capable of reproducing immunization response kinetics. Model definition is achieved in part by requiring consistency with available BrdU-labeling and carboxyfluorescein diacetate succinimidyl ester (CFSE)-dilution data. The calibrated model correctly predicts FE as a function of PN. We conclude that feedback-regulated balance of growth and differentiation, although awaiting definite experimental characterization of the hypothetical cells and molecules involved in regulation, can explain the kinetics of CD4 T-cell responses to antigenic stimulation.

SUBMITTER: Bocharov G

PROVIDER: S-EPMC3044411 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Feedback regulation of proliferation vs. differentiation rates explains the dependence of CD4 T-cell expansion on precursor number.

Bocharov Gennady G Quiel Juan J Luzyanina Tatyana T Alon Hagit H Chiglintsev Egor E Chereshnev Valery V Meier-Schellersheim Martin M Paul William E WE Grossman Zvi Z

Proceedings of the National Academy of Sciences of the United States of America 20110203 8

The mechanisms regulating clonal expansion and contraction of T cells in response to immunization remain to be identified. A recent study established that there was a log-linear relation between CD4 T-cell precursor number (PN) and factor of expansion (FE), with a slope of ∼-0.5 over a range of 3-30,000 precursors per mouse. The results suggested inhibition of precursor expansion either by competition for specific antigen-presenting cells or by the action of other antigen-specific cells in the s ...[more]

PMID: 21292990

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Project description:ImportancePhysical abuse and neglect affect a significant number of children in the United States. The 2014 Medicaid expansion, in which several states opted to expand their Medicaid programs, is associated with parental financial stability and access to mental health care.ObjectiveTo determine whether Medicaid expansion is associated with changes in physical abuse and neglect rates.Design, setting, and participantsThis ecological study used state-level National Child Abuse and Neglect Data Systems (NCANDS) data from January 1, 2010, through December 31, 2016, to compare the change in physical abuse and neglect rates in states that chose to expand Medicaid vs those that did not. All cases of physical abuse and neglect of children younger than 6 years during the study period that were referred to state-level Child Protective Services and screened in for further intervention after having met a maltreatment risk threshold were included. Cases with only documented sexual or emotional abuse were excluded. A difference-in-difference analysis was conducted from April 12, 2018, through March 26, 2019.ExposuresState-level Medicaid expansion status.Main outcomes and measuresIncidence rate of screened-in referrals for physical abuse or neglect per 100 000 children younger than 6 years per year by state.ResultsData were analyzed for 31 states and the District of Columbia that expanded Medicaid and 19 states that did not during the study period, with baseline neglect counts of 646 463 and 388 265, respectively. After Medicaid expansion, 422 fewer cases of neglect per 100 000 children younger than 6 years (95% CI, -753 to -91) were reported each year after adjusting for confounders for comparison of postexpansion and preexpansion rates in states that expanded Medicaid contrasting with the change during that time in nonexpansion states. From 2013 to 2016, Medicaid coverage for adults with dependent children increased a median 1.9% (interquartile range, 0.4% to 4.3%) in the states that did not expand Medicaid and 4.2% (interquartile range, 0.9% to 6.0%) in the states that did. No associations were found between Medicaid coverage or Medicaid eligibility criteria and physical abuse or neglect rates.Conclusions and relevanceMedicaid expansion was associated with a reduction in the reported child neglect rate, but not the physical abuse rate. These findings suggest that expanding Medicaid may help prevent child neglect.

Dataset Information

Feedback regulation of proliferation vs. differentiation rates explains the dependence of CD4 T-cell expansion on precursor number.

Publications

Feedback regulation of proliferation vs. differentiation rates explains the dependence of CD4 T-cell expansion on precursor number.

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