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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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CD4+ TEM cells rapidly migrate to reactive lymph nodes in a CD62P-dependent, CXCR3-independent manner. Adoptively transferred TCR transgenic OVA-specific naive T cells were primed by immunization with an s.c. injection of 106 OVA-pulsed syngeneic LPS-matured DCs. 3 wk later, memory CD4+ T cells were enriched from spleens and lymph nodes, and 3 × 106 T cells were injected i.v. into mice in which reactive lymph nodes had been induced 24 h before by injection of 106 syngeneic LPS-matured DCs. Some mice received also an i.p. injection of thioglycolate 48 h before T cell transfer. (a) Relative proportion of DO11.10 CD4+ TCM (CFSE−KJ1-26+CD62L+CD127+) and TEM (CFSE−KJ1-26+CD62L−CD127+) cells in the population before transfer and in the indicated organs 12 h after transfer (percentages are shown). (b) Absolute number of DO11.10 CD4+ TEM (KJ1-26+CD62L−CD127+) cells in reactive lymph nodes of mice 20 or 60 min after T cell transfer. (c) Expression of CD62P ligands and CXCR3 (black lines) on gated CD4+CD62L− TEM cells. The gray dashed lines represent background staining. (d) Percentages of TEM-like cells from wild-type and CXCR3−/− mice in reactive lymph nodes and spleen 24 h after i.v. injection. T cells were mixed at a ratio of 1:1, and 107 cells were injected in each mouse in which a reactive lymph node was produced by s.c. injection of 3 × 106 mature DCs in the footpad. (e) Absolute number of OT-II CD4+ TEM (Ly5.1+CD62L−CD127+) cells in reactive lymph nodes of wild-type C57BL/6 or CD62P/E double-deficient mice. (f) Absolute number of DO11.10 CD4+ TEM (KJ1-26+CD62L−CD127+) cells in reactive lymph nodes of mice 12 h after injection of blocking antibodies to CD62P or CD62E or of isotype-matched control antibodies. Data are the means ± SD of two or three independent experiments each performed with two mice per condition. p-values were obtained with the Student's t test.
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fig3: CD4+ TEM cells rapidly migrate to reactive lymph nodes in a CD62P-dependent, CXCR3-independent manner. Adoptively transferred TCR transgenic OVA-specific naive T cells were primed by immunization with an s.c. injection of 106 OVA-pulsed syngeneic LPS-matured DCs. 3 wk later, memory CD4+ T cells were enriched from spleens and lymph nodes, and 3 × 106 T cells were injected i.v. into mice in which reactive lymph nodes had been induced 24 h before by injection of 106 syngeneic LPS-matured DCs. Some mice received also an i.p. injection of thioglycolate 48 h before T cell transfer. (a) Relative proportion of DO11.10 CD4+ TCM (CFSE−KJ1-26+CD62L+CD127+) and TEM (CFSE−KJ1-26+CD62L−CD127+) cells in the population before transfer and in the indicated organs 12 h after transfer (percentages are shown). (b) Absolute number of DO11.10 CD4+ TEM (KJ1-26+CD62L−CD127+) cells in reactive lymph nodes of mice 20 or 60 min after T cell transfer. (c) Expression of CD62P ligands and CXCR3 (black lines) on gated CD4+CD62L− TEM cells. The gray dashed lines represent background staining. (d) Percentages of TEM-like cells from wild-type and CXCR3−/− mice in reactive lymph nodes and spleen 24 h after i.v. injection. T cells were mixed at a ratio of 1:1, and 107 cells were injected in each mouse in which a reactive lymph node was produced by s.c. injection of 3 × 106 mature DCs in the footpad. (e) Absolute number of OT-II CD4+ TEM (Ly5.1+CD62L−CD127+) cells in reactive lymph nodes of wild-type C57BL/6 or CD62P/E double-deficient mice. (f) Absolute number of DO11.10 CD4+ TEM (KJ1-26+CD62L−CD127+) cells in reactive lymph nodes of mice 12 h after injection of blocking antibodies to CD62P or CD62E or of isotype-matched control antibodies. Data are the means ± SD of two or three independent experiments each performed with two mice per condition. p-values were obtained with the Student's t test.

Mentions: Mouse CD4+ and CD8+ TEM cells lack CCR7 and CD62L and are therefore largely excluded from lymph nodes in the steady state (21–23). However, it is increasingly recognized that lymph nodes undergoing an immune response show an increased cellularity and become capable of recruiting CD8+ TEM and NK cells (27). Recruitment of CD8+ TEM and NK cells is dependent on expression of CXCR3 on migrating cells and coincides with a transient expression of its ligand, CXCL9, on HEVs of reactive lymph nodes (24, 25). To investigate whether CD4+ TEM cells would be also recruited to reactive lymph nodes, we injected i.v. in vivo–generated OVA-specific memory T cells, comprising both TCM (CD127+CD62L+) and TEM (CD127+CD62L−) cells, into syngeneic mice and measured their migration into a reactive lymph node, which had been induced by s.c. injection of LPS-matured DCs, and into a resting lymph node as control (Fig. 3 a). As expected, TCM cells, which represented a minor fraction of the transferred cell population, were highly enriched in resting lymph nodes, accounting for up to 90% of the recruited cells. In contrast, TEM cells were virtually excluded from resting lymph nodes but efficiently migrated into reactive lymph nodes, where they accounted for up to 85% of the migrated cells, a figure similar to that found in the spleen and inflamed peritoneum (Fig. 3 a). Transferred TEM cells were detected in reactive lymph nodes as early as 20 min after i.v. injection (Fig. 3 b), consistent with a direct migration of circulating T cells through HEVs rather than transit from tissues. In addition, 16 h after transfer, TEM cells colocalized with naive T cells in the T cell areas of reactive lymph nodes (Fig. S2, available at http://www.jem.org/cgi/content/full/jem.20081212/DC1).


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)

CD4+ TEM cells rapidly migrate to reactive lymph nodes in a CD62P-dependent, CXCR3-independent manner. Adoptively transferred TCR transgenic OVA-specific naive T cells were primed by immunization with an s.c. injection of 106 OVA-pulsed syngeneic LPS-matured DCs. 3 wk later, memory CD4+ T cells were enriched from spleens and lymph nodes, and 3 × 106 T cells were injected i.v. into mice in which reactive lymph nodes had been induced 24 h before by injection of 106 syngeneic LPS-matured DCs. Some mice received also an i.p. injection of thioglycolate 48 h before T cell transfer. (a) Relative proportion of DO11.10 CD4+ TCM (CFSE−KJ1-26+CD62L+CD127+) and TEM (CFSE−KJ1-26+CD62L−CD127+) cells in the population before transfer and in the indicated organs 12 h after transfer (percentages are shown). (b) Absolute number of DO11.10 CD4+ TEM (KJ1-26+CD62L−CD127+) cells in reactive lymph nodes of mice 20 or 60 min after T cell transfer. (c) Expression of CD62P ligands and CXCR3 (black lines) on gated CD4+CD62L− TEM cells. The gray dashed lines represent background staining. (d) Percentages of TEM-like cells from wild-type and CXCR3−/− mice in reactive lymph nodes and spleen 24 h after i.v. injection. T cells were mixed at a ratio of 1:1, and 107 cells were injected in each mouse in which a reactive lymph node was produced by s.c. injection of 3 × 106 mature DCs in the footpad. (e) Absolute number of OT-II CD4+ TEM (Ly5.1+CD62L−CD127+) cells in reactive lymph nodes of wild-type C57BL/6 or CD62P/E double-deficient mice. (f) Absolute number of DO11.10 CD4+ TEM (KJ1-26+CD62L−CD127+) cells in reactive lymph nodes of mice 12 h after injection of blocking antibodies to CD62P or CD62E or of isotype-matched control antibodies. Data are the means ± SD of two or three independent experiments each performed with two mice per condition. p-values were obtained with the Student's t test.
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fig3: CD4+ TEM cells rapidly migrate to reactive lymph nodes in a CD62P-dependent, CXCR3-independent manner. Adoptively transferred TCR transgenic OVA-specific naive T cells were primed by immunization with an s.c. injection of 106 OVA-pulsed syngeneic LPS-matured DCs. 3 wk later, memory CD4+ T cells were enriched from spleens and lymph nodes, and 3 × 106 T cells were injected i.v. into mice in which reactive lymph nodes had been induced 24 h before by injection of 106 syngeneic LPS-matured DCs. Some mice received also an i.p. injection of thioglycolate 48 h before T cell transfer. (a) Relative proportion of DO11.10 CD4+ TCM (CFSE−KJ1-26+CD62L+CD127+) and TEM (CFSE−KJ1-26+CD62L−CD127+) cells in the population before transfer and in the indicated organs 12 h after transfer (percentages are shown). (b) Absolute number of DO11.10 CD4+ TEM (KJ1-26+CD62L−CD127+) cells in reactive lymph nodes of mice 20 or 60 min after T cell transfer. (c) Expression of CD62P ligands and CXCR3 (black lines) on gated CD4+CD62L− TEM cells. The gray dashed lines represent background staining. (d) Percentages of TEM-like cells from wild-type and CXCR3−/− mice in reactive lymph nodes and spleen 24 h after i.v. injection. T cells were mixed at a ratio of 1:1, and 107 cells were injected in each mouse in which a reactive lymph node was produced by s.c. injection of 3 × 106 mature DCs in the footpad. (e) Absolute number of OT-II CD4+ TEM (Ly5.1+CD62L−CD127+) cells in reactive lymph nodes of wild-type C57BL/6 or CD62P/E double-deficient mice. (f) Absolute number of DO11.10 CD4+ TEM (KJ1-26+CD62L−CD127+) cells in reactive lymph nodes of mice 12 h after injection of blocking antibodies to CD62P or CD62E or of isotype-matched control antibodies. Data are the means ± SD of two or three independent experiments each performed with two mice per condition. p-values were obtained with the Student's t test.
Mentions: Mouse CD4+ and CD8+ TEM cells lack CCR7 and CD62L and are therefore largely excluded from lymph nodes in the steady state (21–23). However, it is increasingly recognized that lymph nodes undergoing an immune response show an increased cellularity and become capable of recruiting CD8+ TEM and NK cells (27). Recruitment of CD8+ TEM and NK cells is dependent on expression of CXCR3 on migrating cells and coincides with a transient expression of its ligand, CXCL9, on HEVs of reactive lymph nodes (24, 25). To investigate whether CD4+ TEM cells would be also recruited to reactive lymph nodes, we injected i.v. in vivo–generated OVA-specific memory T cells, comprising both TCM (CD127+CD62L+) and TEM (CD127+CD62L−) cells, into syngeneic mice and measured their migration into a reactive lymph node, which had been induced by s.c. injection of LPS-matured DCs, and into a resting lymph node as control (Fig. 3 a). As expected, TCM cells, which represented a minor fraction of the transferred cell population, were highly enriched in resting lymph nodes, accounting for up to 90% of the recruited cells. In contrast, TEM cells were virtually excluded from resting lymph nodes but efficiently migrated into reactive lymph nodes, where they accounted for up to 85% of the migrated cells, a figure similar to that found in the spleen and inflamed peritoneum (Fig. 3 a). Transferred TEM cells were detected in reactive lymph nodes as early as 20 min after i.v. injection (Fig. 3 b), consistent with a direct migration of circulating T cells through HEVs rather than transit from tissues. In addition, 16 h after transfer, TEM cells colocalized with naive T cells in the T cell areas of reactive lymph nodes (Fig. S2, available at http://www.jem.org/cgi/content/full/jem.20081212/DC1).

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