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CD40L+ CD4+ memory T cells migrate in a CD62P-dependent fashion into reactive lymph nodes and license dendritic cells for T cell priming.

Martín-Fontecha A, Baumjohann D, Guarda G, Reboldi A, Hons M, Lanzavecchia A, Sallusto F - J. Exp. Med. (2008)

Bottom Line: CD4(+) T(EM) cells were excluded from resting lymph nodes but migrated in a CD62P-dependent fashion into reactive lymph nodes that were induced to express CD62P, in a transient or sustained fashion, on high endothelial venules.Antibodies to CD62P, which blocked CD4(+) T(EM) cell migration into reactive lymph nodes, inhibited DC maturation, T cell priming, and induction of EAE.These results show that T(EM) cells can behave as endogenous adjuvants and suggest a mechanistic link between lymphocyte traffic in lymph nodes and induction of autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland. alfonso.martin-fontecha@kcl.ac.uk

ABSTRACT
There is growing evidence that the maturation state of dendritic cells (DCs) is a critical parameter determining the balance between tolerance and immunity. We report that mouse CD4(+) effector memory T (T(EM)) cells, but not naive or central memory T cells, constitutively expressed CD40L at levels sufficient to induce DC maturation in vitro and in vivo in the absence of antigenic stimulation. CD4(+) T(EM) cells were excluded from resting lymph nodes but migrated in a CD62P-dependent fashion into reactive lymph nodes that were induced to express CD62P, in a transient or sustained fashion, on high endothelial venules. Trafficking of CD4(+) T(EM) cells into chronic reactive lymph nodes maintained resident DCs in a mature state and promoted naive T cell responses and experimental autoimmune encephalomyelitis (EAE) to antigens administered in the absence of adjuvants. Antibodies to CD62P, which blocked CD4(+) T(EM) cell migration into reactive lymph nodes, inhibited DC maturation, T cell priming, and induction of EAE. These results show that T(EM) cells can behave as endogenous adjuvants and suggest a mechanistic link between lymphocyte traffic in lymph nodes and induction of autoimmunity.

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EAE can be induced by presentation of MOG peptides in reactive lymph nodes and is inhibited by CD62P blockade. Groups of mice (n = 16), either untreated (a and b) or that had received 30 d earlier an s.c. injection of CFA or two consecutive s.c. injections of LPS-matured DCs to induce a chronic reactive lymph node (c and d), were challenged i.v. with 100 μg MOG35-55 peptide in CFA (a) or in PBS (b–d). For each experimental group, half of the mice received once a week an i.v. injection of 100 μg CD62P antibodies (circles) or isotype matched control antibodies (squares) for the entire duration of the experiment. Mice were graded daily for clinical manifestation of EAE. Shown are mean clinical scores of eight mice per group. Error bars represent the SE for each point. (right) CD4 expression on lymphocytes isolated from the brain and spinal cords of mice 20 d after priming with MOG peptide. Numbers are the percentage of the gated population. Results are representative of two separate experiments.
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fig6: EAE can be induced by presentation of MOG peptides in reactive lymph nodes and is inhibited by CD62P blockade. Groups of mice (n = 16), either untreated (a and b) or that had received 30 d earlier an s.c. injection of CFA or two consecutive s.c. injections of LPS-matured DCs to induce a chronic reactive lymph node (c and d), were challenged i.v. with 100 μg MOG35-55 peptide in CFA (a) or in PBS (b–d). For each experimental group, half of the mice received once a week an i.v. injection of 100 μg CD62P antibodies (circles) or isotype matched control antibodies (squares) for the entire duration of the experiment. Mice were graded daily for clinical manifestation of EAE. Shown are mean clinical scores of eight mice per group. Error bars represent the SE for each point. (right) CD4 expression on lymphocytes isolated from the brain and spinal cords of mice 20 d after priming with MOG peptide. Numbers are the percentage of the gated population. Results are representative of two separate experiments.

Mentions: Injection of MOG peptide in CFA led to rapid development of clinical symptoms of EAE and to accumulation of CD4+ T cells in the central nervous system, whereas injection of MOG peptide in PBS did not result in any clinical symptoms or T cell infiltrate (Fig. 6, a and b). Remarkably, injection of MOG peptide in PBS in mice carrying a reactive lymph node, which had been induced by injection of either CFA or mature DCs 1 mo earlier, led to the development of clinical symptoms and T cell infiltrates that were comparable in severity and extent to those induced by the administration of MOG in CFA (Fig. 6, c and d). Pretreatment of mice with anti-CD62P antibodies did not interfere with EAE induced by immunization with MOG peptide in CFA (Fig. 6 a), consistent with the fact that CD62P is not required for migration of effector T cells into the brain (29). Remarkably, however, anti-CD62P treatment prevented EAE and T cell infiltration in the central nervous system induced by injection of MOG peptide in PBS draining into reactive lymph nodes (Fig. 6, c and d). Collectively, these data are consistent with a model in which CD4+ TEM cells recruited into reactive lymph nodes provide a licensing signal to resident DCs that facilitates response to self-antigens and the development of pathogenic autoreactive T cells.


CD40L+ CD4+ memory T cells migrate in a CD62P-dependent fashion into reactive lymph nodes and license dendritic cells for T cell priming.

Martín-Fontecha A, Baumjohann D, Guarda G, Reboldi A, Hons M, Lanzavecchia A, Sallusto F - J. Exp. Med. (2008)

EAE can be induced by presentation of MOG peptides in reactive lymph nodes and is inhibited by CD62P blockade. Groups of mice (n = 16), either untreated (a and b) or that had received 30 d earlier an s.c. injection of CFA or two consecutive s.c. injections of LPS-matured DCs to induce a chronic reactive lymph node (c and d), were challenged i.v. with 100 μg MOG35-55 peptide in CFA (a) or in PBS (b–d). For each experimental group, half of the mice received once a week an i.v. injection of 100 μg CD62P antibodies (circles) or isotype matched control antibodies (squares) for the entire duration of the experiment. Mice were graded daily for clinical manifestation of EAE. Shown are mean clinical scores of eight mice per group. Error bars represent the SE for each point. (right) CD4 expression on lymphocytes isolated from the brain and spinal cords of mice 20 d after priming with MOG peptide. Numbers are the percentage of the gated population. Results are representative of two separate experiments.
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Related In: Results  -  Collection

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fig6: EAE can be induced by presentation of MOG peptides in reactive lymph nodes and is inhibited by CD62P blockade. Groups of mice (n = 16), either untreated (a and b) or that had received 30 d earlier an s.c. injection of CFA or two consecutive s.c. injections of LPS-matured DCs to induce a chronic reactive lymph node (c and d), were challenged i.v. with 100 μg MOG35-55 peptide in CFA (a) or in PBS (b–d). For each experimental group, half of the mice received once a week an i.v. injection of 100 μg CD62P antibodies (circles) or isotype matched control antibodies (squares) for the entire duration of the experiment. Mice were graded daily for clinical manifestation of EAE. Shown are mean clinical scores of eight mice per group. Error bars represent the SE for each point. (right) CD4 expression on lymphocytes isolated from the brain and spinal cords of mice 20 d after priming with MOG peptide. Numbers are the percentage of the gated population. Results are representative of two separate experiments.
Mentions: Injection of MOG peptide in CFA led to rapid development of clinical symptoms of EAE and to accumulation of CD4+ T cells in the central nervous system, whereas injection of MOG peptide in PBS did not result in any clinical symptoms or T cell infiltrate (Fig. 6, a and b). Remarkably, injection of MOG peptide in PBS in mice carrying a reactive lymph node, which had been induced by injection of either CFA or mature DCs 1 mo earlier, led to the development of clinical symptoms and T cell infiltrates that were comparable in severity and extent to those induced by the administration of MOG in CFA (Fig. 6, c and d). Pretreatment of mice with anti-CD62P antibodies did not interfere with EAE induced by immunization with MOG peptide in CFA (Fig. 6 a), consistent with the fact that CD62P is not required for migration of effector T cells into the brain (29). Remarkably, however, anti-CD62P treatment prevented EAE and T cell infiltration in the central nervous system induced by injection of MOG peptide in PBS draining into reactive lymph nodes (Fig. 6, c and d). Collectively, these data are consistent with a model in which CD4+ TEM cells recruited into reactive lymph nodes provide a licensing signal to resident DCs that facilitates response to self-antigens and the development of pathogenic autoreactive T cells.

Bottom Line: CD4(+) T(EM) cells were excluded from resting lymph nodes but migrated in a CD62P-dependent fashion into reactive lymph nodes that were induced to express CD62P, in a transient or sustained fashion, on high endothelial venules.Antibodies to CD62P, which blocked CD4(+) T(EM) cell migration into reactive lymph nodes, inhibited DC maturation, T cell priming, and induction of EAE.These results show that T(EM) cells can behave as endogenous adjuvants and suggest a mechanistic link between lymphocyte traffic in lymph nodes and induction of autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland. alfonso.martin-fontecha@kcl.ac.uk

ABSTRACT
There is growing evidence that the maturation state of dendritic cells (DCs) is a critical parameter determining the balance between tolerance and immunity. We report that mouse CD4(+) effector memory T (T(EM)) cells, but not naive or central memory T cells, constitutively expressed CD40L at levels sufficient to induce DC maturation in vitro and in vivo in the absence of antigenic stimulation. CD4(+) T(EM) cells were excluded from resting lymph nodes but migrated in a CD62P-dependent fashion into reactive lymph nodes that were induced to express CD62P, in a transient or sustained fashion, on high endothelial venules. Trafficking of CD4(+) T(EM) cells into chronic reactive lymph nodes maintained resident DCs in a mature state and promoted naive T cell responses and experimental autoimmune encephalomyelitis (EAE) to antigens administered in the absence of adjuvants. Antibodies to CD62P, which blocked CD4(+) T(EM) cell migration into reactive lymph nodes, inhibited DC maturation, T cell priming, and induction of EAE. These results show that T(EM) cells can behave as endogenous adjuvants and suggest a mechanistic link between lymphocyte traffic in lymph nodes and induction of autoimmunity.

Show MeSH
Related in: MedlinePlus