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In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines.

Ansel KM, McHeyzer-Williams LJ, Ngo VN, McHeyzer-Williams MG, Cyster JG - J. Exp. Med. (1999)

Bottom Line: At the same time, the CXCR5(hi) cells showed reduced responsiveness to the T zone chemokines, Epstein-Barr virus-induced molecule 1 (EBI-1) ligand chemokine (ELC) and secondary lymphoid tissue chemokine (SLC).After adoptive transfer, CXCR5(hi) CD4 T cells did not migrate to follicles, indicating that additional changes may occur after immunization that help direct T cells to follicles.Taken together, our findings indicate that reprogramming of responsiveness to constitutively expressed lymphoid tissue chemokines plays an important role in T cell migration to the B cell compartment of lymphoid tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California 94143, USA.

ABSTRACT
Migration of antigen-activated CD4 T cells to B cell areas of lymphoid tissues is important for mounting T cell-dependent antibody responses. Here we show that CXC chemokine receptor (CXCR)5, the receptor for B lymphocyte chemoattractant (BLC), is upregulated on antigen-specific CD4 T cells in vivo when animals are immunized under conditions that promote T cell migration to follicles. In situ hybridization of secondary follicles for BLC showed high expression in mantle zones and low expression in germinal centers. When tested directly ex vivo, CXCR5(hi) T cells exhibited a vigorous chemotactic response to BLC. At the same time, the CXCR5(hi) cells showed reduced responsiveness to the T zone chemokines, Epstein-Barr virus-induced molecule 1 (EBI-1) ligand chemokine (ELC) and secondary lymphoid tissue chemokine (SLC). After adoptive transfer, CXCR5(hi) CD4 T cells did not migrate to follicles, indicating that additional changes may occur after immunization that help direct T cells to follicles. To further explore whether T cells could acquire an intrinsic ability to migrate to follicles, CD4(-)CD8(-) double negative (DN) T cells from MRL-lpr mice were studied. These T cells normally accumulate within follicles of MRL-lpr mice. Upon transfer to wild-type recipients, DN T cells migrated to follicle proximal regions in all secondary lymphoid tissues. Taken together, our findings indicate that reprogramming of responsiveness to constitutively expressed lymphoid tissue chemokines plays an important role in T cell migration to the B cell compartment of lymphoid tissues.

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Chemotactic response profiles of in vivo–activated OVA-specific T cells and memory phenotype CXCR5-expressing T cells. Results are expressed as percentage of transmigrated input cells. Bars represent means of duplicate transwells. (A) Chemotaxis of KJ1-26+CD4+ OVA-specific (black bars) and nonspecific CD4+ (white bars) cells from draining LNs of OVA-specific T cell transfer recipients immunized 7 d previously with OVA peptide subcutaneously in CFA. Chemokine concentrations were: BLC, 2 μg/ml; ELC, 0.2 μg/ml; SLC, 0.2 μg/ml; and SDF1, 0.3 μg/ml. Results were similar at day 5 after immunization and are representative of at least three independent experiments for each chemokine. (B) Response of KJ1-26+CD4+ OVA-specific (black bars) and nonspecific CD4+ (white bars) cells to 0.2 μg/ml ELC. Cells are from draining LNs of transfer recipients immunized with OVA peptide subcutaneously in CFA (solid bars) or intravenously in saline (hatched bars). The day after immunization is indicated on the x-axis. Data at day 5 are representative of five experiments for subcutaneous immunization in CFA and two experiments for intravenous immunization in saline. (C) Chemotaxis of CXCR5lo/− (white bars) and CXCR5hi (black bars) CD4+ T cells from the spleen of a 21-mo-old mouse. Chemokine concentrations were: BLC, 2 μg/ml; ELC, 0.5 μg/ml; SLC, 0.8 μg/ml; and SDF1, 0.3 μg/ml. Results are representative of at least four independent experiments for each chemokine. CXCR5hi T cells exhibited reduced responsiveness to ELC (0.02–1.5 μg/ml) and SLC (0.08–1.2 μg/ml) at all chemokine concentrations tested.
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Figure 5: Chemotactic response profiles of in vivo–activated OVA-specific T cells and memory phenotype CXCR5-expressing T cells. Results are expressed as percentage of transmigrated input cells. Bars represent means of duplicate transwells. (A) Chemotaxis of KJ1-26+CD4+ OVA-specific (black bars) and nonspecific CD4+ (white bars) cells from draining LNs of OVA-specific T cell transfer recipients immunized 7 d previously with OVA peptide subcutaneously in CFA. Chemokine concentrations were: BLC, 2 μg/ml; ELC, 0.2 μg/ml; SLC, 0.2 μg/ml; and SDF1, 0.3 μg/ml. Results were similar at day 5 after immunization and are representative of at least three independent experiments for each chemokine. (B) Response of KJ1-26+CD4+ OVA-specific (black bars) and nonspecific CD4+ (white bars) cells to 0.2 μg/ml ELC. Cells are from draining LNs of transfer recipients immunized with OVA peptide subcutaneously in CFA (solid bars) or intravenously in saline (hatched bars). The day after immunization is indicated on the x-axis. Data at day 5 are representative of five experiments for subcutaneous immunization in CFA and two experiments for intravenous immunization in saline. (C) Chemotaxis of CXCR5lo/− (white bars) and CXCR5hi (black bars) CD4+ T cells from the spleen of a 21-mo-old mouse. Chemokine concentrations were: BLC, 2 μg/ml; ELC, 0.5 μg/ml; SLC, 0.8 μg/ml; and SDF1, 0.3 μg/ml. Results are representative of at least four independent experiments for each chemokine. CXCR5hi T cells exhibited reduced responsiveness to ELC (0.02–1.5 μg/ml) and SLC (0.08–1.2 μg/ml) at all chemokine concentrations tested.

Mentions: T cells have been shown to respond strongly to ELC and SLC in in vitro chemotaxis assays 22232427282930. Since these chemokines are expressed in the T zone and might be able to counteract the ability of a cell to respond to a chemokine made in follicles, we tested whether CXCR5-expressing T cells were altered in their responsiveness to ELC and SLC. In striking contrast to the elevated ELC and SLC responsiveness of in vitro–activated T cells 282930, OVA-specific T cells activated in vivo by subcutaneous peptide/CFA injection showed a significant downregulation in responsiveness to these T zone chemokines (Fig. 5 A). The time course of this decreased responsiveness to ELC (Fig. 5 B) was similar to the time course over which the cells became responsive to BLC (Fig. 4 B). In contrast, OVA-specific T cells from mice immunized intravenously with peptide in saline maintained their ability to respond to ELC throughout the 10-d time course (Fig. 5 B). Responsiveness to SDF1 was also decreased in the in vivo–activated T cells (Fig. 5 A), consistent with the recent in vitro finding that anti-CD3 stimulation reduces responsiveness to SDF1 38. CXCR5-expressing memory phenotype cells from aged mice showed similarly low responsiveness to ELC and SLC (Fig. 5 C). Interestingly, in these cells the responsiveness to SDF1 was elevated (Fig. 5 C).


In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines.

Ansel KM, McHeyzer-Williams LJ, Ngo VN, McHeyzer-Williams MG, Cyster JG - J. Exp. Med. (1999)

Chemotactic response profiles of in vivo–activated OVA-specific T cells and memory phenotype CXCR5-expressing T cells. Results are expressed as percentage of transmigrated input cells. Bars represent means of duplicate transwells. (A) Chemotaxis of KJ1-26+CD4+ OVA-specific (black bars) and nonspecific CD4+ (white bars) cells from draining LNs of OVA-specific T cell transfer recipients immunized 7 d previously with OVA peptide subcutaneously in CFA. Chemokine concentrations were: BLC, 2 μg/ml; ELC, 0.2 μg/ml; SLC, 0.2 μg/ml; and SDF1, 0.3 μg/ml. Results were similar at day 5 after immunization and are representative of at least three independent experiments for each chemokine. (B) Response of KJ1-26+CD4+ OVA-specific (black bars) and nonspecific CD4+ (white bars) cells to 0.2 μg/ml ELC. Cells are from draining LNs of transfer recipients immunized with OVA peptide subcutaneously in CFA (solid bars) or intravenously in saline (hatched bars). The day after immunization is indicated on the x-axis. Data at day 5 are representative of five experiments for subcutaneous immunization in CFA and two experiments for intravenous immunization in saline. (C) Chemotaxis of CXCR5lo/− (white bars) and CXCR5hi (black bars) CD4+ T cells from the spleen of a 21-mo-old mouse. Chemokine concentrations were: BLC, 2 μg/ml; ELC, 0.5 μg/ml; SLC, 0.8 μg/ml; and SDF1, 0.3 μg/ml. Results are representative of at least four independent experiments for each chemokine. CXCR5hi T cells exhibited reduced responsiveness to ELC (0.02–1.5 μg/ml) and SLC (0.08–1.2 μg/ml) at all chemokine concentrations tested.
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Figure 5: Chemotactic response profiles of in vivo–activated OVA-specific T cells and memory phenotype CXCR5-expressing T cells. Results are expressed as percentage of transmigrated input cells. Bars represent means of duplicate transwells. (A) Chemotaxis of KJ1-26+CD4+ OVA-specific (black bars) and nonspecific CD4+ (white bars) cells from draining LNs of OVA-specific T cell transfer recipients immunized 7 d previously with OVA peptide subcutaneously in CFA. Chemokine concentrations were: BLC, 2 μg/ml; ELC, 0.2 μg/ml; SLC, 0.2 μg/ml; and SDF1, 0.3 μg/ml. Results were similar at day 5 after immunization and are representative of at least three independent experiments for each chemokine. (B) Response of KJ1-26+CD4+ OVA-specific (black bars) and nonspecific CD4+ (white bars) cells to 0.2 μg/ml ELC. Cells are from draining LNs of transfer recipients immunized with OVA peptide subcutaneously in CFA (solid bars) or intravenously in saline (hatched bars). The day after immunization is indicated on the x-axis. Data at day 5 are representative of five experiments for subcutaneous immunization in CFA and two experiments for intravenous immunization in saline. (C) Chemotaxis of CXCR5lo/− (white bars) and CXCR5hi (black bars) CD4+ T cells from the spleen of a 21-mo-old mouse. Chemokine concentrations were: BLC, 2 μg/ml; ELC, 0.5 μg/ml; SLC, 0.8 μg/ml; and SDF1, 0.3 μg/ml. Results are representative of at least four independent experiments for each chemokine. CXCR5hi T cells exhibited reduced responsiveness to ELC (0.02–1.5 μg/ml) and SLC (0.08–1.2 μg/ml) at all chemokine concentrations tested.
Mentions: T cells have been shown to respond strongly to ELC and SLC in in vitro chemotaxis assays 22232427282930. Since these chemokines are expressed in the T zone and might be able to counteract the ability of a cell to respond to a chemokine made in follicles, we tested whether CXCR5-expressing T cells were altered in their responsiveness to ELC and SLC. In striking contrast to the elevated ELC and SLC responsiveness of in vitro–activated T cells 282930, OVA-specific T cells activated in vivo by subcutaneous peptide/CFA injection showed a significant downregulation in responsiveness to these T zone chemokines (Fig. 5 A). The time course of this decreased responsiveness to ELC (Fig. 5 B) was similar to the time course over which the cells became responsive to BLC (Fig. 4 B). In contrast, OVA-specific T cells from mice immunized intravenously with peptide in saline maintained their ability to respond to ELC throughout the 10-d time course (Fig. 5 B). Responsiveness to SDF1 was also decreased in the in vivo–activated T cells (Fig. 5 A), consistent with the recent in vitro finding that anti-CD3 stimulation reduces responsiveness to SDF1 38. CXCR5-expressing memory phenotype cells from aged mice showed similarly low responsiveness to ELC and SLC (Fig. 5 C). Interestingly, in these cells the responsiveness to SDF1 was elevated (Fig. 5 C).

Bottom Line: At the same time, the CXCR5(hi) cells showed reduced responsiveness to the T zone chemokines, Epstein-Barr virus-induced molecule 1 (EBI-1) ligand chemokine (ELC) and secondary lymphoid tissue chemokine (SLC).After adoptive transfer, CXCR5(hi) CD4 T cells did not migrate to follicles, indicating that additional changes may occur after immunization that help direct T cells to follicles.Taken together, our findings indicate that reprogramming of responsiveness to constitutively expressed lymphoid tissue chemokines plays an important role in T cell migration to the B cell compartment of lymphoid tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California 94143, USA.

ABSTRACT
Migration of antigen-activated CD4 T cells to B cell areas of lymphoid tissues is important for mounting T cell-dependent antibody responses. Here we show that CXC chemokine receptor (CXCR)5, the receptor for B lymphocyte chemoattractant (BLC), is upregulated on antigen-specific CD4 T cells in vivo when animals are immunized under conditions that promote T cell migration to follicles. In situ hybridization of secondary follicles for BLC showed high expression in mantle zones and low expression in germinal centers. When tested directly ex vivo, CXCR5(hi) T cells exhibited a vigorous chemotactic response to BLC. At the same time, the CXCR5(hi) cells showed reduced responsiveness to the T zone chemokines, Epstein-Barr virus-induced molecule 1 (EBI-1) ligand chemokine (ELC) and secondary lymphoid tissue chemokine (SLC). After adoptive transfer, CXCR5(hi) CD4 T cells did not migrate to follicles, indicating that additional changes may occur after immunization that help direct T cells to follicles. To further explore whether T cells could acquire an intrinsic ability to migrate to follicles, CD4(-)CD8(-) double negative (DN) T cells from MRL-lpr mice were studied. These T cells normally accumulate within follicles of MRL-lpr mice. Upon transfer to wild-type recipients, DN T cells migrated to follicle proximal regions in all secondary lymphoid tissues. Taken together, our findings indicate that reprogramming of responsiveness to constitutively expressed lymphoid tissue chemokines plays an important role in T cell migration to the B cell compartment of lymphoid tissues.

Show MeSH
Related in: MedlinePlus