cytokines ͉ inflammasome ͉ Th1 ͉ Th17 ͉ Th2

Antigen-driven expansion of specific CD4 T cells diminishes, on a per cell basis, as infused cell number increases. There is a linear relation between log precursor number and log factor of expansion (FE), with a slope of ∼−0.5 over a range from 3 to 30,000 precursors. Cell number dependence of FE is observed at low precursor number, implying that the underlying process physiologically regulates antigen-driven T-cell expansion. FE of small numbers of transgenic precursors is not significantly affected by concomitant responses of large numbers of cells specific for different antigens. Increasing antigen amount or exogenous IL-2, IL-7, or IL-15 does not significantly affect FE, nor does FE depend on Fas, TNF-α receptor, cytotoxic T-lymphocyte antigen-4, IL-2, or IFN-γ. Small numbers of Foxp3-deficient T-cell receptor transgenic cells expand to a greater extent than do large numbers, implying that this effect is not mediated by regulatory T cells. Increasing dendritic cell number does result in larger FE, but the quantitative relation between FE and precursor number is not abrogated. Although not excluding competition for peptide/MHC complexes as an explanation, fall in FE with increasing precursor number could be explained by a negative feedback in which increasing numbers of responding cells in a cluster inhibit the expansion of cells of the same specificity within that cluster. cytokine | T-cell clusterT -cell responses to antigens are characterized by rapid expansion in numbers of specific cells, followed by a steep contraction phase and then a relative stabilization at frequencies above those in the naive cell population (1-5). We show here and others have previously reported that the factor of expansion (FE), the ratio of the number of antigen-specific cells at 7 d after immunization to the number before immunization, is dependent on the number of cells transferred (3-6). Here, we report that over a range of precursor frequencies ranging from 3 to 30,000 among lymph node T cells, there is a log-linear relation between precursor number and FE, with a slope of ∼−0.5. Estimates of the physiological frequency of antigen-specific precursors range from 20 to 3,000 per animal, corresponding to frequencies ranging from 0.2 to 30 per 100,000 naive CD4 T cells (7-10). Thus, the fall in FE described here occurs within the physiological range of precursor number and must reflect a fundamental property of antigen-mediated immune responses.

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. time delay | parameter estimation I n response to cognate antigens, specific T-cell numbers rapidly increase and then steeply decline, approaching relatively stable frequencies higher than those in the naive cell population (1-4). What determines the magnitude of the response? Several conceptual frameworks have been proposed: predator-prey-like interaction between lymphocytes and antigen (5-8), cell-autonomous expansion and contraction following a brief priming (9-14), and cell population-level feedback control (15-18).The first concept inspired the development of a broad range of mathematical cell-population models to describe the dynamics of the response to viruses and bacteria with the view of antigen (the prey) as the sole, positive regulator of the proliferation, differentiation, and death of lymphocytes (the predator). Criticism of this approach can be found in ref. 19. The second concept, antigeninitiated, but not antigen-driven, expansion and contraction, does not appear to apply to CD4 T cells, which require the continued presence of antigen to proliferate (20,21). Note that such a requirement for antigen does not necessarily imply antigen-mediated control of the duration and size of the immune response; these parameters could still be determined ...