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Molecular and Cellular Biology, June 2008, p. 4040-4051, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.00136-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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

Departments of Chemical Engineering,¹ Chemistry,² Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139,³ Department of Pathology and Immune Disease Institute; Harvard Medical School, 77 Louis Pasteur Avenue, Boston, Massachusetts 02115,⁴ Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico 87545⁵

Received 24 January 2008/ Returned for modification 10 February 2008/ Accepted 4 April 2008

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.

Published ahead of print on 21 April 2008.

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