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. 2002 Oct;110(8):1113-21.
doi: 10.1172/JCI15988.

"V体育2025版" CCL25 mediates the localization of recently activated CD8alphabeta(+) lymphocytes to the small-intestinal mucosa

Marcus Svensson  1 , Jan Marsal, Anna Ericsson, Laura Carramolino, Therese Brodén, Gabriel Márquez, William W Agace
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"VSports注册入口" CCL25 mediates the localization of recently activated CD8alphabeta(+) lymphocytes to the small-intestinal mucosa

"VSports在线直播" Marcus Svensson et al. J Clin Invest. 2002 Oct.

VSports - Abstract

The recruitment of antigen-specific T lymphocytes to the intestinal mucosa is central to the development of an effective mucosal immune response, yet the mechanism by which this process occurs remains to be fully defined. Here we show that the CC chemokine receptor 9 (CCR9) is selectively and functionally expressed on murine alpha(E)beta(7)(+) naive CD8alphabeta(+) lymphocytes and a subset of recently activated CD69(+) CD8alphabeta(+) lymphocytes. Using a T cell receptor transgenic transfer model, we demonstrate that CCR9 expression is functionally maintained on CD8alphabeta(+) lymphocytes following activation in mesenteric lymph nodes but rapidly downregulated on CD8alphabeta(+) lymphocytes activated in peripheral lymph nodes VSports手机版. These recently activated CCR9(+) CD8alphabeta(+) lymphocytes selectively localized to the small-intestinal mucosa, and in vivo neutralization of the CCR9 ligand, CCL25, reduced the ability of these cells to populate the small-intestinal epithelium. Together these results demonstrate an important role for chemokines in the localization of T lymphocytes to the small-intestinal mucosa and suggest that targeting CCL25 and/or CCR9 may provide a means to selectively modulate small-intestinal immune responses. .

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Figures

Figure 1
Figure 1
CCR9 expression on murine lymphocytes from normal mice. (a) CD8+ and CD4+ lymphocytes from MLNs were stained with anti-CCR9 antibody (open) or anti-CCR9 antibody that had been preincubated with the CCR9-immunizing peptide (shaded). Numbers represent percentage of CCR9+ cells with background staining removed. Background staining was consistently less than 2%. (b) CCR9+ CD8αβ+ lymphocytes coexpress αEβ7 integrin. (c) CD8αβ+ αEβ7+, but not CD8αβ+ αEβ7–, lymphocytes migrate to CCL25. The ability of CD8αβ+ αEβ7+ and CD8αβ+ αEβ7– lymphocytes to migrate to CCL25 (250 nM) or CXCL12 (100 nM) was determined in chemotaxis assays (see Methods). Results are mean ± SEM of quadruplicate wells from one experiment of two performed. *P < 0.0001. (d) CCR9 expression on CD8αβ+ lymphocyte subsets in MLNs. Numbers represent percentage of CCR9+ cells with background staining removed.
Figure 2
Figure 2
Regulation of CCR9 expression on antigen-specific CD8αβ+ lymphocytes following activation in vivo. (a) OT-1 (Ly5.2+) cells were injected into C57BL/6J-Ly5.1 mice, and their expression of CCR9 was determined by flow cytometry 3 days after intraperitoneal OVA administration. Numbers represent the percentage of OT-1 cells that are CCR9+ with background staining removed. Results are from one representative experiment of nine (MLN), seven (PLN), and two (spleen) experiments performed. (b) OT-1 cells from the MLNs of OVA-treated mice respond to CCL25. MLN and PLN lymphocytes were isolated 3 days after intraperitoneal administration of OVA, and the ability of OT-1 cells and endogenous CD8αβ+ lymphocytes to migrate to CCL25 (250 nM) was determined. Results are the mean ± SEM of four experiments with three mice per experiment. *P < 0.005.
Figure 3
Figure 3
CCR9 is maintained on a subset of OT-1 cells following activation in MLNs. (a) CCR9 expression on CFSE+ CD8αβ+ OT-1 (Ly5.2+) lymphocytes. OT-1 cells were labeled with CFSE and injected into C57BL/6J-Ly5.1 mice. MLNs and PLNs were removed 2 days after intraperitoneal administration with OVA plus LPS, and the expression of CCR9 on CFSE+ OT-1 cells was determined by flow cytometry. Results are from one representative experiment of four performed with pooled cells from three to five mice. (b) Combined results of CCR9 expression on OT-1 cells from MLNs (filled symbols) and PLNs (open symbols) 2 days after stimulation with OVA plus LPS. Each symbol represents the mean ± SEM of three to four experiments with cells pooled from three to five mice per experiment. The data from cells that had undergone no divisions and one division are from two experiments, since there were too few cells for analysis in the remaining two experiments. *P < 0.02, **P < 0.002. (c) CCR9 expression on OT-1 (Ly5.2+, CD8αβ+) cells 3 days after stimulation with OVA plus LPS. Results are from the same experiment as in a and are representative of three performed.
Figure 4
Figure 4
Activated CCR9+ OT-1 cells selectively localize to the small intestine. (a) CCR9 expression on CD8αβ+ lymphocytes isolated from tissue effector sites. Cells were stained with anti-CCR9 antibody (open) or anti-CCR9 antibody that had been preincubated with the CCR9-immunizing peptide (shaded), and analyzed by flow cytometry. Results are representative stainings from six mice for small-intestinal and colonic IELs and three mice for small-intestinal LPLs. Skin CD8αβ+ lymphocytes were obtained from the ears of mice with 2,4-dinitro-1-fluorobenzene–induced DTH and are from two stainings using ears pooled from a total of 40 mice. Numbers represent percentage of CD8αβ+ lymphocytes that are CCR9+ with background staining removed. (b) OT-1 cells (Ly5.2+) were injected into C57BL/6J-Ly5.1 mice. Three days after intraperitoneal administration of OVA, lymphocytes were isolated from the small intestine, and the expression of CCR9 on OT-1 lymphocytes was determined by flow cytometry. Results are from five (IEL) and one (LPL) separate stainings using a total of eleven and three mice respectively. Numbers represent the percentage of OT-1 cells expressing CCR9 with background staining removed. (c) CCL25 is selectively expressed in the murine small intestine (SI). Quantitative analysis of CCL25 mRNA expression was determined by real-time RT-PCR.
Figure 5
Figure 5
Anti-CCL25 antibody reduces OT-1 cell recruitment to the small-intestinal epithelium. OT-1 (Ly 5.2+) cells were injected into C57BL/6J-Ly5.1 mice, and the percentage of CD8β+ lymphocytes expressing Ly5.2 in the MLNs (a), PLNs (b), liver (c), and small intestine (d) of control or anti-CCL25 antibody–treated mice was determined by flow cytometry 3 days after intraperitoneal challenge with OVA. Results are the mean ± SEM of six (PLN, MLN, liver) and four (small intestine) mice in each group and show one representative experiment of three performed. *P < 0.05. (e) Representative flow cytometry analysis of the small-intestinal IEL populations in each group of mice.
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