How Antigen Quantity and Quality Determine T-Cell Decisions in Lymphoid Tissue

Abstract

T lymphocytes (T cells) express T-cell receptor (TCR) molecules on their surface that can recognize peptides (p) derived from antigenic proteins bound to products of the major histocompatibility complex (MHC) genes. The pMHC molecules are expressed on the surface of antigen-presenting cells, such as dendritic cells (DCs). T cells first encounter antigen on DCs in lymph nodes (LN). Intravital microscopy experiments show that upon entering the LN containing antigen, CD8؉ T cells first move rapidly. After a few hours, they stop and make extended contacts with DCs. The factors that determine when and how this transition occurs are not well understood. We report results from computer simulations that suggest that the duration of phase one is related to the low probability of productive interactions between T cells and DCs. This is demonstrated by our finding that the antigen dose and type determine when such a transition occurs. These results are in agreement with experimental observations. TCR-pMHC binding characteristics and the antigen dose determine the time required for a productive T-cell-DC encounter (resulting in sustained contact). We find that the ratio of this time scale and the half-life of the pMHC complex itself provide a consolidated measure of antigen quantity and type. Results obtained upon varying different measures of antigen quantity and type fall on one curve when graphed against this ratio of time scales. Thus, we provide a mechanism for how the effects of varying one set of parameters are influenced by other prevailing conditions. This understanding should help guide future experimentation.Recent multiphoton and confocal microscopy experiments have produced vivid images of the migration of T cells in lymphoid tissues during antigen recognition (2, 6-8, 11, 23, 30, 32-34, 37, 38, 40, 43, 47). For both CD4 and CD8 T cells, the motility characteristics change with time. Initially, T cells move quite rapidly upon entering the lymph node (LN). In the presence of cognate antigen, after a few hours, antigen-specific T cells slow down and make stable contacts with dendritic cells (DCs) presenting cognate antigen (6,23,30,32,33,37,38,40). For CD8 T cells, these two stages of different T-cell motility have been labeled "phase one" and "phase two" behavior (30). It seems reasonable to assume that phase one corresponds to a period during which T cells "hunt" for antigen, whereas phase two is a period of time required for signaling processes that result in a full commitment to activation (30,33). An important open question is which factors determine the time required for the transition from phase one to phase two. This is important, since this decision predicates T-cell activation and the initiation of an immune response.Several hypotheses could be considered to address this question. One is that T cells may go through such motility changes by default (30). This hypothesis implies that all antigen-specific T cells in the LN would transition into phase two synchronously and that the time at which this happe...

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