The race for the prize: T-cell trafficking strategies for optimal surveillance

Abstract

The initiation of T-cell responses requires rare precursors to locate a draining lymph node (dLN) and encounter dendritic cells (DCs) presenting peptide-major histocompatibility complexes (pMHCs). To locate this needle in the haystack rapidly, T cells face an optimization problem-what is the most efficient trafficking strategy for surveillance and recirculation through blood? Two extremes are scanning low numbers of DCs per node with frequent recirculation, or meticulous surveillance with infrequent recirculation. Naive T cells also require stimulation by self-pMHCs. To enable efficient location of both foreign and self, has evolution settled on an optimum time for T cells to spend surveying each lymph node? Using a datadriven mathematical model, we show the most efficient strategy for detecting antigen in a dLN depends on its abundance. Detection of low-density antigen is optimized with systemically slow transit. In contrast, at high densities or if dLN egress is restricted, rapid transit through other nodes is optimal. We argue that bloodlymph recirculation dynamics facilitate a trade-off, and are consistent with dominant roles for the very early detection of rare foreign antigens in a dLN, and the efficient accumulation of signals from systemically distributed self-antigens. (Blood. 2012;120(7):1432-1438) IntroductionNaive T cells have the task of surveying both for foreign antigens and for weak interactions with self, which are required for optimal function. 1-3 Recognition of both takes place in lymph nodes, exquisitely constructed environments that facilitate the encounter of T and B lymphocytes with antigens. In mice, the naive CD4 and CD4 T-cell pools each comprise roughly 5 ϫ 10 7 cells, but the diversity of T-cell receptor (TCR) sequences is such that a remarkably small proportion are capable of recognizing a given antigen with sufficient affinity to reach an activation threshold. Estimates of the typical antigen-specific pool size in mice are in the range 10 to 1200 cells. [4][5][6][7][8][9] A high degree of polyclonality ensures both broad coverage and fine specificity of the TCR repertoire, but comes at the price of increasing the time required for the relevant cells in the total repertoire to locate a given peptide-MHC complex.In their search for TCR stimulation, naive T cells circulate continuously through the spleen, lymph nodes, lymphatic vessels, and blood. 10 At steady state, naive T cells enter lymph nodes from the blood at random through the high endothelial venules (HEVs), taking a few minutes to cross into the lymph node cortex. 11,12 There they encounter and survey DC presenting peptide-MHC ligands. While in the cortical region, T cells acquire competence to egress, at most 4 hours, 13 but possibly as little as 20 minutes 14 after crossing the HEV. T cells exit from the lymph node through lymphatic sinuses and return to the blood, first through lymphatics, and finally through the thoracic duct. Smith and Ford studied lymphocyte recirculation in rats and found that intravenously injected c...

Quantification of lymph node transit times reveals differences in antigen surveillance strategies of naïve CD4 + and CD8 + T cells

“…It is likely that T-cell transit times and precursor frequencies are optimized to ensure that foreign antigens are detected rapidly enough for effective pathogen clearance. If preimmune precursor population sizes were approximately equivalent between CD4 + and CD8 + T cells, the accelerated recirculation kinetics of CD4 + T cells might mean that they have an increased probability of locating an LN in which there is foreign antigen, but a reduced probability of detecting it within a given LN, compared with CD8 + T cells (36). However, precursor frequencies of CD4 + T cells may on average be lower than that of CD8 + T cells (37,38).…”

Topological Small-World Organization of the Fibroblastic Reticular Cell Network Determines Lymph Node Functionality

“…Several modeling approaches have been described that focus on the description of processes that occur in LN subcompartments such as DC-driven T cell migration [48] or differentiation of Th cell subsets [49]. However, in order to obtain a more holistic view on LN functionality, the complexity of multilayered processes needs to be captured in mathematical models, an endeavor that requires representation of the whole LN [50].…”

Spatiotemporal Basis of Innate and Adaptive Immunity in Secondary Lymphoid Tissue

“…This scheme does impose important restrictions on the rates of LN entry and exit and the length and efficiency of the scanning process if an unacceptable delay in initiation of adaptive immunity is to be avoided (Lee et al 2012. It also requires that pathogens do not replicate freely during the several days it takes for rare lymphocytes to locate antigen, become activated, proliferate to adequate numbers, and develop effector function so that they can participate in pathogen clearance.…”