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Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization.

Gunn MD, Kyuwa S, Tam C, Kakiuchi T, Matsuzawa A, Williams LT, Nakano H - J. Exp. Med. (1999)

Bottom Line: Secondary lymphoid organ chemokine (SLC) is expressed in high endothelial venules and in T cell zones of spleen and lymph nodes (LNs) and strongly attracts naive T cells.DC migration to LNs after contact sensitization is also substantially reduced.The plt mutation maps to the SLC locus; however, the sequence of SLC introns and exons in plt mice is normal.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research Institute, University of California San Francisco, San Francisco, California 94143, USA. michael.gunn@duke.edu

ABSTRACT
Secondary lymphoid organ chemokine (SLC) is expressed in high endothelial venules and in T cell zones of spleen and lymph nodes (LNs) and strongly attracts naive T cells. In mice homozygous for the paucity of lymph node T cell (plt) mutation, naive T cells fail to home to LNs or the lymphoid regions of spleen. Here we demonstrate that expression of SLC is undetectable in plt mice. In addition to the defect in T cell homing, we demonstrate that dendritic cells (DCs) fail to accumulate in spleen and LN T cell zones of plt mice. DC migration to LNs after contact sensitization is also substantially reduced. The physiologic significance of these abnormalities in plt mice is indicated by a markedly increased sensitivity to infection with murine hepatitis virus. The plt mutation maps to the SLC locus; however, the sequence of SLC introns and exons in plt mice is normal. These findings suggest that the abnormalities in plt mice are due to a genetic defect in the expression of SLC and that SLC mediates the entry of naive T cells and antigen-stimulated DCs into the T cell zones of secondary lymphoid organs.

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Expression of ELC  mRNA is decreased in the LNs  and spleens of plt mice. Tissues  from +/+ (A and C) and plt (B  and D) mice were analyzed as  described in the legend to Fig. 1.  ELC hybridization signal (white  dots) can be seen in LN (A) and  spleen (C) of +/+ mice. The  intensity of ELC signal is reduced in the LN (B) and spleen  (D) of plt mice. f, lymphoid follicles; RP, red pulp. (E) Northern  blot analysis. Total RNA from  peripheral LNs (PLN) and spleen  of +/+ and plt mice was hybridized with 32P-labeled ELC probe  and subjected to autoradiography. Blots were stripped and  reprobed with actin probe to determine variability in gel loading.
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Figure 7: Expression of ELC mRNA is decreased in the LNs and spleens of plt mice. Tissues from +/+ (A and C) and plt (B and D) mice were analyzed as described in the legend to Fig. 1. ELC hybridization signal (white dots) can be seen in LN (A) and spleen (C) of +/+ mice. The intensity of ELC signal is reduced in the LN (B) and spleen (D) of plt mice. f, lymphoid follicles; RP, red pulp. (E) Northern blot analysis. Total RNA from peripheral LNs (PLN) and spleen of +/+ and plt mice was hybridized with 32P-labeled ELC probe and subjected to autoradiography. Blots were stripped and reprobed with actin probe to determine variability in gel loading.

Mentions: ELC is the chemokine most closely related to SLC. ELC and SLC have similar activities; both activate the CCR7 receptor, and their genes are located within 100 kb of each other in the human genome (24, 39, 40). In contrast to SLC, ELC expression is limited to interdigitating DCs in LNs and spleen (41). To determine if the decreased accumulation of DCs in plt mice leads to a decrease in the production of ELC, we examined ELC expression in plt mice. By Northern analysis, ELC mRNA levels in the LNs and spleen of plt mice were reduced compared with +/+ mice (Fig. 7 E). By in situ hybridization, ELC expression was reduced in the LNs of plt mice compared with +/+ mice (Fig. 7, A and B). ELC antisense probes hybridized most strongly to the outer LN cortex in a region corresponding to the area in which DCs accumulated in plt mice (compare Fig. 7 B and Fig. 3 B). In the spleens of plt mice, ELC expression was also reduced (Fig. 7, C and D). As in LNs, the hybridization signal in plt spleen localized to regions that correspond to the area in which DCs accumulated (compare Fig. 7 D and Fig. 3 D). Similar to results in +/+ mice, no ELC signal was detected in lymphatics or any nonlymphoid tissue of plt mice (data not shown).


Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization.

Gunn MD, Kyuwa S, Tam C, Kakiuchi T, Matsuzawa A, Williams LT, Nakano H - J. Exp. Med. (1999)

Expression of ELC  mRNA is decreased in the LNs  and spleens of plt mice. Tissues  from +/+ (A and C) and plt (B  and D) mice were analyzed as  described in the legend to Fig. 1.  ELC hybridization signal (white  dots) can be seen in LN (A) and  spleen (C) of +/+ mice. The  intensity of ELC signal is reduced in the LN (B) and spleen  (D) of plt mice. f, lymphoid follicles; RP, red pulp. (E) Northern  blot analysis. Total RNA from  peripheral LNs (PLN) and spleen  of +/+ and plt mice was hybridized with 32P-labeled ELC probe  and subjected to autoradiography. Blots were stripped and  reprobed with actin probe to determine variability in gel loading.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2192914&req=5

Figure 7: Expression of ELC mRNA is decreased in the LNs and spleens of plt mice. Tissues from +/+ (A and C) and plt (B and D) mice were analyzed as described in the legend to Fig. 1. ELC hybridization signal (white dots) can be seen in LN (A) and spleen (C) of +/+ mice. The intensity of ELC signal is reduced in the LN (B) and spleen (D) of plt mice. f, lymphoid follicles; RP, red pulp. (E) Northern blot analysis. Total RNA from peripheral LNs (PLN) and spleen of +/+ and plt mice was hybridized with 32P-labeled ELC probe and subjected to autoradiography. Blots were stripped and reprobed with actin probe to determine variability in gel loading.
Mentions: ELC is the chemokine most closely related to SLC. ELC and SLC have similar activities; both activate the CCR7 receptor, and their genes are located within 100 kb of each other in the human genome (24, 39, 40). In contrast to SLC, ELC expression is limited to interdigitating DCs in LNs and spleen (41). To determine if the decreased accumulation of DCs in plt mice leads to a decrease in the production of ELC, we examined ELC expression in plt mice. By Northern analysis, ELC mRNA levels in the LNs and spleen of plt mice were reduced compared with +/+ mice (Fig. 7 E). By in situ hybridization, ELC expression was reduced in the LNs of plt mice compared with +/+ mice (Fig. 7, A and B). ELC antisense probes hybridized most strongly to the outer LN cortex in a region corresponding to the area in which DCs accumulated in plt mice (compare Fig. 7 B and Fig. 3 B). In the spleens of plt mice, ELC expression was also reduced (Fig. 7, C and D). As in LNs, the hybridization signal in plt spleen localized to regions that correspond to the area in which DCs accumulated (compare Fig. 7 D and Fig. 3 D). Similar to results in +/+ mice, no ELC signal was detected in lymphatics or any nonlymphoid tissue of plt mice (data not shown).

Bottom Line: Secondary lymphoid organ chemokine (SLC) is expressed in high endothelial venules and in T cell zones of spleen and lymph nodes (LNs) and strongly attracts naive T cells.DC migration to LNs after contact sensitization is also substantially reduced.The plt mutation maps to the SLC locus; however, the sequence of SLC introns and exons in plt mice is normal.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research Institute, University of California San Francisco, San Francisco, California 94143, USA. michael.gunn@duke.edu

ABSTRACT
Secondary lymphoid organ chemokine (SLC) is expressed in high endothelial venules and in T cell zones of spleen and lymph nodes (LNs) and strongly attracts naive T cells. In mice homozygous for the paucity of lymph node T cell (plt) mutation, naive T cells fail to home to LNs or the lymphoid regions of spleen. Here we demonstrate that expression of SLC is undetectable in plt mice. In addition to the defect in T cell homing, we demonstrate that dendritic cells (DCs) fail to accumulate in spleen and LN T cell zones of plt mice. DC migration to LNs after contact sensitization is also substantially reduced. The physiologic significance of these abnormalities in plt mice is indicated by a markedly increased sensitivity to infection with murine hepatitis virus. The plt mutation maps to the SLC locus; however, the sequence of SLC introns and exons in plt mice is normal. These findings suggest that the abnormalities in plt mice are due to a genetic defect in the expression of SLC and that SLC mediates the entry of naive T cells and antigen-stimulated DCs into the T cell zones of secondary lymphoid organs.

Show MeSH
Related in: MedlinePlus