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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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TEM cells migrating into reactive lymph nodes maintain DCs in a mature immunostimulatory state. (a, d, and g) Experimental design. (a) Mice were transferred with Thy1.1+ DO11.10 OVA-specific T cells and either left untreated or primed with one or two s.c. injections of OVA-pulsed DCs to generate TEM cells and acute or chronic reactive lymph nodes. Some mice were injected weekly with 100 μg of control antibodies or anti-CD62P blocking antibodies. (b) Expression of CD40 and MHC class II on CD11c+ DCs purified 30 d after priming from resting (gray lines) or reactive (black lines) lymph nodes. (c) On day 30, mice were transferred with CFSE-labeled HA-specific 6.5 naive T cells and challenged with an i.v. injection of 10 μg HA in PBS. Shown are the percentages and the CFSE profiles of 6.5+ T cells in resting or reactive lymph nodes 5 d after challenge. (d) Mice received an s.c. injection of CFA to generate chronic reactive lymph nodes. Control mice received an s.c. injection of PBS. (e) Expression of CD40 and MHC class II on CD11c+ DCs purified 30 d after priming from resting or chronic reactive lymph nodes. (f) On day 30, mice were transferred with CFSE-labeled 6.5 naive T cells and challenged with an i.v. injection of 10 μg of HA protein in PBS. Shown are the percentages and the CFSE profiles of 6.5+ T cells in resting or chronic reactive lymph nodes 5 d after challenge. (g) Naive mice were adoptively transferred with CFSE-labeled 6.5 naive T cells, and a reactive lymph node was induced by s.c. injection of LPS. 5 d later, mice received an s.c. injection of HA in PBS together with an i.v. transfer of DO11.10 TEM cells that had been treated with control or CD40L-blocking antibodies. (h) Proliferative response of 6.5+ T cells in reactive lymph nodes in the absence or presence of untreated or anti-CD40L–treated TEM cells. Results are representative of two to five separate experiments.
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fig5: TEM cells migrating into reactive lymph nodes maintain DCs in a mature immunostimulatory state. (a, d, and g) Experimental design. (a) Mice were transferred with Thy1.1+ DO11.10 OVA-specific T cells and either left untreated or primed with one or two s.c. injections of OVA-pulsed DCs to generate TEM cells and acute or chronic reactive lymph nodes. Some mice were injected weekly with 100 μg of control antibodies or anti-CD62P blocking antibodies. (b) Expression of CD40 and MHC class II on CD11c+ DCs purified 30 d after priming from resting (gray lines) or reactive (black lines) lymph nodes. (c) On day 30, mice were transferred with CFSE-labeled HA-specific 6.5 naive T cells and challenged with an i.v. injection of 10 μg HA in PBS. Shown are the percentages and the CFSE profiles of 6.5+ T cells in resting or reactive lymph nodes 5 d after challenge. (d) Mice received an s.c. injection of CFA to generate chronic reactive lymph nodes. Control mice received an s.c. injection of PBS. (e) Expression of CD40 and MHC class II on CD11c+ DCs purified 30 d after priming from resting or chronic reactive lymph nodes. (f) On day 30, mice were transferred with CFSE-labeled 6.5 naive T cells and challenged with an i.v. injection of 10 μg of HA protein in PBS. Shown are the percentages and the CFSE profiles of 6.5+ T cells in resting or chronic reactive lymph nodes 5 d after challenge. (g) Naive mice were adoptively transferred with CFSE-labeled 6.5 naive T cells, and a reactive lymph node was induced by s.c. injection of LPS. 5 d later, mice received an s.c. injection of HA in PBS together with an i.v. transfer of DO11.10 TEM cells that had been treated with control or CD40L-blocking antibodies. (h) Proliferative response of 6.5+ T cells in reactive lymph nodes in the absence or presence of untreated or anti-CD40L–treated TEM cells. Results are representative of two to five separate experiments.

Mentions: The finding that under certain conditions recruitment of TEM cells in lymph nodes can be sustained for several weeks suggests the possibility that these cells might influence the DC maturation state through the constitutive expression of CD40L. To test this possibility, mice were transferred with Thy1.1+ OVA-specific DO11.10 naive T cells and primed with one or two consecutive s.c. injections of OVA-pulsed DCs (OVA-DC 1× and OVA-DC 2×, respectively) to generate TEM cells and to induce an acute or a chronic reactive lymph node (Fig. 5 a). Some mice were injected weekly with anti-CD62P blocking antibodies or isotype-matched control antibodies to inhibit TEM cell migration and the induction of chronic reactive lymph nodes. 30 d after priming, high numbers of DO11.10 TEM cells were recovered from chronic reactive but not acute reactive lymph nodes (Fig. S5, available at http://www.jem.org/cgi/content/full/jem.20081212/DC1). Interestingly, on day 30 after priming all DCs recovered from chronic reactive lymph nodes expressed increased levels of CD40 and MHC class II molecules as compared with DCs recovered from resting or acute reactive lymph nodes (Fig. 5 b). At this late time point, there was no evidence of persisting OVA antigen in reactive lymph nodes, as shown by the lack of proliferation of i.v.-injected CFSE-labeled OT-II T cells (unpublished data). Strikingly, in mice treated with blocking CD62P antibodies, DCs did not show increased expression of CD40 and MHC class II molecules (Fig. 5 b). These results are consistent with a role for lymph node–migrating CD4+ TEM cells in the induction of DC maturation in vivo.


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)

TEM cells migrating into reactive lymph nodes maintain DCs in a mature immunostimulatory state. (a, d, and g) Experimental design. (a) Mice were transferred with Thy1.1+ DO11.10 OVA-specific T cells and either left untreated or primed with one or two s.c. injections of OVA-pulsed DCs to generate TEM cells and acute or chronic reactive lymph nodes. Some mice were injected weekly with 100 μg of control antibodies or anti-CD62P blocking antibodies. (b) Expression of CD40 and MHC class II on CD11c+ DCs purified 30 d after priming from resting (gray lines) or reactive (black lines) lymph nodes. (c) On day 30, mice were transferred with CFSE-labeled HA-specific 6.5 naive T cells and challenged with an i.v. injection of 10 μg HA in PBS. Shown are the percentages and the CFSE profiles of 6.5+ T cells in resting or reactive lymph nodes 5 d after challenge. (d) Mice received an s.c. injection of CFA to generate chronic reactive lymph nodes. Control mice received an s.c. injection of PBS. (e) Expression of CD40 and MHC class II on CD11c+ DCs purified 30 d after priming from resting or chronic reactive lymph nodes. (f) On day 30, mice were transferred with CFSE-labeled 6.5 naive T cells and challenged with an i.v. injection of 10 μg of HA protein in PBS. Shown are the percentages and the CFSE profiles of 6.5+ T cells in resting or chronic reactive lymph nodes 5 d after challenge. (g) Naive mice were adoptively transferred with CFSE-labeled 6.5 naive T cells, and a reactive lymph node was induced by s.c. injection of LPS. 5 d later, mice received an s.c. injection of HA in PBS together with an i.v. transfer of DO11.10 TEM cells that had been treated with control or CD40L-blocking antibodies. (h) Proliferative response of 6.5+ T cells in reactive lymph nodes in the absence or presence of untreated or anti-CD40L–treated TEM cells. Results are representative of two to five separate experiments.
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fig5: TEM cells migrating into reactive lymph nodes maintain DCs in a mature immunostimulatory state. (a, d, and g) Experimental design. (a) Mice were transferred with Thy1.1+ DO11.10 OVA-specific T cells and either left untreated or primed with one or two s.c. injections of OVA-pulsed DCs to generate TEM cells and acute or chronic reactive lymph nodes. Some mice were injected weekly with 100 μg of control antibodies or anti-CD62P blocking antibodies. (b) Expression of CD40 and MHC class II on CD11c+ DCs purified 30 d after priming from resting (gray lines) or reactive (black lines) lymph nodes. (c) On day 30, mice were transferred with CFSE-labeled HA-specific 6.5 naive T cells and challenged with an i.v. injection of 10 μg HA in PBS. Shown are the percentages and the CFSE profiles of 6.5+ T cells in resting or reactive lymph nodes 5 d after challenge. (d) Mice received an s.c. injection of CFA to generate chronic reactive lymph nodes. Control mice received an s.c. injection of PBS. (e) Expression of CD40 and MHC class II on CD11c+ DCs purified 30 d after priming from resting or chronic reactive lymph nodes. (f) On day 30, mice were transferred with CFSE-labeled 6.5 naive T cells and challenged with an i.v. injection of 10 μg of HA protein in PBS. Shown are the percentages and the CFSE profiles of 6.5+ T cells in resting or chronic reactive lymph nodes 5 d after challenge. (g) Naive mice were adoptively transferred with CFSE-labeled 6.5 naive T cells, and a reactive lymph node was induced by s.c. injection of LPS. 5 d later, mice received an s.c. injection of HA in PBS together with an i.v. transfer of DO11.10 TEM cells that had been treated with control or CD40L-blocking antibodies. (h) Proliferative response of 6.5+ T cells in reactive lymph nodes in the absence or presence of untreated or anti-CD40L–treated TEM cells. Results are representative of two to five separate experiments.
Mentions: The finding that under certain conditions recruitment of TEM cells in lymph nodes can be sustained for several weeks suggests the possibility that these cells might influence the DC maturation state through the constitutive expression of CD40L. To test this possibility, mice were transferred with Thy1.1+ OVA-specific DO11.10 naive T cells and primed with one or two consecutive s.c. injections of OVA-pulsed DCs (OVA-DC 1× and OVA-DC 2×, respectively) to generate TEM cells and to induce an acute or a chronic reactive lymph node (Fig. 5 a). Some mice were injected weekly with anti-CD62P blocking antibodies or isotype-matched control antibodies to inhibit TEM cell migration and the induction of chronic reactive lymph nodes. 30 d after priming, high numbers of DO11.10 TEM cells were recovered from chronic reactive but not acute reactive lymph nodes (Fig. S5, available at http://www.jem.org/cgi/content/full/jem.20081212/DC1). Interestingly, on day 30 after priming all DCs recovered from chronic reactive lymph nodes expressed increased levels of CD40 and MHC class II molecules as compared with DCs recovered from resting or acute reactive lymph nodes (Fig. 5 b). At this late time point, there was no evidence of persisting OVA antigen in reactive lymph nodes, as shown by the lack of proliferation of i.v.-injected CFSE-labeled OT-II T cells (unpublished data). Strikingly, in mice treated with blocking CD62P antibodies, DCs did not show increased expression of CD40 and MHC class II molecules (Fig. 5 b). These results are consistent with a role for lymph node–migrating CD4+ TEM cells in the induction of DC maturation in vivo.

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