Antigen-stimulated CD4 T-cell expansion is inversely and log-linearly related to precursor number

Abstract

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.

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

“…Remarkably, this relationship existed already in the physiologic range of very small PN, e.g., when the number of TCR-transgenic CD4 T cells that homed to lymph nodes after being transferred to mice increased from 3 to 30, representing an increase in the frequency from ∼1/3,300,000 to 1/330,000 (assuming 10 million lymph node CD4 T cells). A similar decrease in FE was observed in experiments comparing 30 and 300 precursors and those comparing 300 and 30,000 precursors (23).…”

“…Defining the factor of expansion (FE) as the ratio between the number of antigen-specific cells at 7 d after immunization and the number of precursors (PN), it has been reported very recently that, over four orders of magnitude of PN, the relation between the change in FE in response to immunization and the change in PN was log-linear. Log(FE) fell by slightly less than half a log for each log increase in PN, with an r 2 of 0.79 (23). This result means that when PN increased n-fold in this range, the fold decrease in FE was approximately sqrt(n).…”

Weakly self‐reactive T‐cell clones can homeostatically expand when present at low numbers

“…It is well-established that T-cell division during antigen-specific responses is a function of the number of the antigen-specific T cells present, such that large numbers of T cells with the same TCR inhibits their expansion [8,9]. There is also evidence that T cells compete for the sub-threshold self-pMHC signals critical to T-cell maintenance.…”

“…On average, naïve T cells are long-lived, but both in humans and mice there is continual turnover with cells dying and being replaced. Two sources of renewal contribute to naïve T-cell maintenance: de novo production in the thymus and proliferation within secondary inhibits their expansion [8,9]. There is also evidence that T cells compete for the sub-threshold self-pMHC signals critical to T-cell maintenance.…”

“…Moreover, restoration of naïve T-cell numbers after acute T-cell depletion, whether caused by infection, chemotherapy, or bone marrow transplantation requires cell division. Both naïve T-cell division and cell survival are dependent on extrinsic cues provided by IL-7 and tonic trophic signals obtained via the T-cell receptor (TCR) through interaction with specific self-pMHC [2][3][4][5][6][7].It is well-established that T-cell division during antigen-specific responses is a function of the number of the antigen-specific T cells present, such that large numbers of T cells with the same TCR inhibits their expansion [8,9]. There is also evidence that T cells compete for the sub-threshold self-pMHC signals critical to T-cell maintenance.…”