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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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CD40L+ CD4+ TEM cells license DCs for T cell priming in vitro. (a) Proliferation of CFSE-labeled HA-specific 6.5 transgenic naive CD4+ T cells cultured with 50 μM HA110-119–pulsed syngeneic immature DCs in the absence or presence of ex vivo–isolated OVA-specific DO11.10 transgenic CD4+ T naive, TCM, or TEM cells. (b) Proliferation of CFSE-labeled OVA-specific OT-II transgenic naive CD4+ T cells cultured with 0.1 μM OVA323-339–pulsed syngeneic immature DCs in the absence or presence of ex vivo–isolated polyclonal T naive, TCM, or TEM cells. (c) Proliferation of CFSE-labeled OVA-specific OT-II transgenic naive CD4+ T cells cultured with polyclonal TEM cells in the presence of OVA-pulsed wild-type or CD40−/− immature DCs. Shown is the CFSE profile of T cells measured on day 5. Results are representative of at least three independent experiments.
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fig2: CD40L+ CD4+ TEM cells license DCs for T cell priming in vitro. (a) Proliferation of CFSE-labeled HA-specific 6.5 transgenic naive CD4+ T cells cultured with 50 μM HA110-119–pulsed syngeneic immature DCs in the absence or presence of ex vivo–isolated OVA-specific DO11.10 transgenic CD4+ T naive, TCM, or TEM cells. (b) Proliferation of CFSE-labeled OVA-specific OT-II transgenic naive CD4+ T cells cultured with 0.1 μM OVA323-339–pulsed syngeneic immature DCs in the absence or presence of ex vivo–isolated polyclonal T naive, TCM, or TEM cells. (c) Proliferation of CFSE-labeled OVA-specific OT-II transgenic naive CD4+ T cells cultured with polyclonal TEM cells in the presence of OVA-pulsed wild-type or CD40−/− immature DCs. Shown is the CFSE profile of T cells measured on day 5. Results are representative of at least three independent experiments.

Mentions: We next asked whether TEM cell–matured DCs would be capable of priming naive T cells. Hemagglutinin (HA) peptide–pulsed immature DCs were cultured with CFSE-labeled HA-specific 6.5 TCR transgenic CD4+ naive T cells alone or together with naive T, TCM, and TEM cells specific for a different antigen (DO11.10 TCR transgenic T cells recognizing OVA). HA-specific naive T cells did not proliferate when stimulated with HA-pulsed immature DCs (Fig. 2 a), consistent with the notion that immature DCs have poor co-stimulatory capacity and fail to prime naive T cells (26). However, these cells proliferated vigorously and differentiated to IFN-γ–producing effector T cells when stimulated with immature DCs in the presence of OVA-specific TEM cells but not naive T or TCM cells (Fig. 2 a and not depicted). Similarly, CFSE-labeled OVA-specific CD4+ naive T cells proliferated in response to OVA-pulsed immature DCs when cultured with polyclonal CD4+ TEM cells but not naive T or TCM cells (Fig. 2 b). Finally, in the presence of polyclonal CD4+ TEM cells, OVA-specific CD4+ naive T cells proliferated in response to OVA peptide presented by wild-type but not CD40−/− DCs (Fig. 2 c). The results of these in vitro experiments indicate that CD4+ TEM cells can license immature DCs for priming of naive T cells in an antigen-independent and CD40-dependent fashion, and raise the question of whether CD4+ TEM cells might induce 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)

CD40L+ CD4+ TEM cells license DCs for T cell priming in vitro. (a) Proliferation of CFSE-labeled HA-specific 6.5 transgenic naive CD4+ T cells cultured with 50 μM HA110-119–pulsed syngeneic immature DCs in the absence or presence of ex vivo–isolated OVA-specific DO11.10 transgenic CD4+ T naive, TCM, or TEM cells. (b) Proliferation of CFSE-labeled OVA-specific OT-II transgenic naive CD4+ T cells cultured with 0.1 μM OVA323-339–pulsed syngeneic immature DCs in the absence or presence of ex vivo–isolated polyclonal T naive, TCM, or TEM cells. (c) Proliferation of CFSE-labeled OVA-specific OT-II transgenic naive CD4+ T cells cultured with polyclonal TEM cells in the presence of OVA-pulsed wild-type or CD40−/− immature DCs. Shown is the CFSE profile of T cells measured on day 5. Results are representative of at least three independent experiments.
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fig2: CD40L+ CD4+ TEM cells license DCs for T cell priming in vitro. (a) Proliferation of CFSE-labeled HA-specific 6.5 transgenic naive CD4+ T cells cultured with 50 μM HA110-119–pulsed syngeneic immature DCs in the absence or presence of ex vivo–isolated OVA-specific DO11.10 transgenic CD4+ T naive, TCM, or TEM cells. (b) Proliferation of CFSE-labeled OVA-specific OT-II transgenic naive CD4+ T cells cultured with 0.1 μM OVA323-339–pulsed syngeneic immature DCs in the absence or presence of ex vivo–isolated polyclonal T naive, TCM, or TEM cells. (c) Proliferation of CFSE-labeled OVA-specific OT-II transgenic naive CD4+ T cells cultured with polyclonal TEM cells in the presence of OVA-pulsed wild-type or CD40−/− immature DCs. Shown is the CFSE profile of T cells measured on day 5. Results are representative of at least three independent experiments.
Mentions: We next asked whether TEM cell–matured DCs would be capable of priming naive T cells. Hemagglutinin (HA) peptide–pulsed immature DCs were cultured with CFSE-labeled HA-specific 6.5 TCR transgenic CD4+ naive T cells alone or together with naive T, TCM, and TEM cells specific for a different antigen (DO11.10 TCR transgenic T cells recognizing OVA). HA-specific naive T cells did not proliferate when stimulated with HA-pulsed immature DCs (Fig. 2 a), consistent with the notion that immature DCs have poor co-stimulatory capacity and fail to prime naive T cells (26). However, these cells proliferated vigorously and differentiated to IFN-γ–producing effector T cells when stimulated with immature DCs in the presence of OVA-specific TEM cells but not naive T or TCM cells (Fig. 2 a and not depicted). Similarly, CFSE-labeled OVA-specific CD4+ naive T cells proliferated in response to OVA-pulsed immature DCs when cultured with polyclonal CD4+ TEM cells but not naive T or TCM cells (Fig. 2 b). Finally, in the presence of polyclonal CD4+ TEM cells, OVA-specific CD4+ naive T cells proliferated in response to OVA peptide presented by wild-type but not CD40−/− DCs (Fig. 2 c). The results of these in vitro experiments indicate that CD4+ TEM cells can license immature DCs for priming of naive T cells in an antigen-independent and CD40-dependent fashion, and raise the question of whether CD4+ TEM cells might induce 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