Figure 3: Possible mechanisms to explain the proliferation by naı ¨ve T cells in response to low-affinity ligands following T-cell depletion.

The lymphopenic state renders naı ¨ve T cells capable of responding by proliferation to peptide–MHC complexes that are not stimulatory during normal conditions. a, Competition for niches or space on the antigen-presenting cell (APC) would be reduced when T-cell numbers are depleted, thereby allowing greater accessibility to ligands or growth factors. Such decreased competition for non-MHC-derived stimulatory signals such as growth factors or ligands could make signals accessible that would allow T cells to detect self-peptide–MHC complexes resulting in proliferation. It seems improbable that a decrease in direct competition for peptide–MHC complexes explains the ability of T cells to proliferate in response to self-peptide–MHC ligands because CD4⁺ and CD8⁺ T cells recognize distinct ligands yet appear to occupy largely overlapping homeostatic niches. b, T cells could somehow ‘sense’ a drop in T-cell number. T cell/T cell interactions could inhibit proliferation or decrease sensitivity to TCR signals. A release from autoinhibition during lymphopenia would allow T cells to receive a signal for proliferation following interactions with low-affinity ligands for the TCR. c, T-cell loss could be detected by another cell type that would upregulate the expression of a factor promoting T-cell division by influencing the T-cell response or sensitivity to TCR interactions with low-affinity peptide–MHC ligands.