Cutting edge: latecomer CD8 T cells are imprinted with a unique differentiation program - PubMed (original) (raw)

Cutting edge: latecomer CD8 T cells are imprinted with a unique differentiation program

Warren N D'Souza et al. J Immunol. 2006.

Abstract

Factors that influence T cell responses, such as Ag load, APCs, costimulatory molecules, and cytokines, dramatically change during the course of an immune response. We observed that antiviral CD8 T cells were not recruited from circulation simultaneously, but over a period of 3-4 days. Consequently, locally resident T cells and those that entered secondary lymphoid tissue later were primed in very different environments. The cells recruited later in the response were imprinted with a unique differentiation program, such that their magnitude of proliferation was reduced and their kinetics of expansion was delayed. In addition, we found that the "latecomer" CD8 T cells displayed a unique surface phenotype indicative of reduced stimulation but were not preferentially recruited into the surviving pool of memory cells. This finding demonstrates that the timing of recruitment of individual T cell clones determines the population dynamics of the subsequent immune response.

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Figures

FIGURE 1

FIGURE 1

Antiviral CD8 T cells are not recruited simultaneously. CFSE-labeled OT-I/RAG−/−/CD45.1+ cells (1 × 106) were transferred to B6 (CD45.2+) hosts that were left unimmunized or were immunized with VSVOVA a day later. A, Percentage of naive donor cells in PBL was measured over time. B, Donor cell numbers present within immunized mice were expressed as a percentage of those in unimmunized animals. The values plotted represent the mean ± SD.

FIGURE 2

FIGURE 2

Latecomer CD8 T cells exhibit a diminished and delayed peak of expansion. Four groups of B6 (CD45.2+) mice were immunized with VSV-OVA on day 0. One group of mice did not receive any OT-I cells, whereas the other three groups received OT-I cells on day −1, day +2, or day +4, respectively. The endogenous response to OVA (Endog) in the mice that did not receive any OT-I cells (None) or in those that received OT-I cells at indicated time points (d(−1), d(+ 2), and d(+4), representing days −1, +2, and +4, respectively) was tracked using MHC class I tetramers (Kb-SIINFEKL), whereas the presence of the donor OT-I cells was determined using the congenic marker CD45.1. A_−_C, Mice were analyzed at indicated time points following infection, and numbers were plotted as a percentage of total PBL. The response within the mice that did not receive any OT-I cells (None Endog) is plotted again in B and C for reference. D and E, The expansion and contraction of each subpopulation was normalized to the peak of expansion.

FIGURE 3

FIGURE 3

Latecomer cells display a phenotype indicative of reduced stimulation. Experiments were performed as in Fig. 2, where mice received day −1 or day +2 OT-I cells and were immunized with VSV-OVA at day 0. The expression of CD62L (L-selectin) (A) and that of CD25, KLRG1, and CD127 (IL-7Rα)(B) on the OT-I cells in the spleen were determined at days 6, 7, 8, and 9 postinfection. In B, the normalized response kinetics taken from Fig. 2_E_ (percent peak) are plotted for reference along with the percentage of donor cells expressing the indicated markers. Also indicated (left panel) is the expression of the cell surface markers on naive OT-I cells before transfer.

FIGURE 4

FIGURE 4

Similar proportions of latecomer T cells survive the contraction phase. Experiments were performed as in Fig. 2. The endogenous and the OT-I responses in PBL were tracked during all phases of the response. A, The efficiency of memory generation was calculated by expressing the proportion of memory cells present in PBL (at day 71) as a percentage of the respective proliferative peaks. B, The expression of CD62L on the indicated cell populations in the spleen was determined at ~3 mo postinfection. Numbers plotted are the percentage of cells that are CD62Lhigh.

FIGURE 5

FIGURE 5

Latecomer T cells are capable of differentiating into functional memory cells. Experiments were performed as in Fig. 2. At ~4 mo postinfection, the percentage of endogenous SIINFEKL-specific cells (tetramer+CD45.1−) and donor OT-I cells (tetramer+CD45.1+) in PBL was determined. The mice were then challenged with Lm-OVA a day later and analyzed at day 7 postchallenge. Cells were gated on CD8+ cells, and the numbers indicated are the percentages of total PBL.

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