Essential role of the TNF-TNFR2 cognate interaction in mouse dendritic cell–natural killer cell crosstalk

Invariant NKT (iNKT) cells play an effector/adjuvant function during antimicrobial and antitumoral immunity and a regulatory role to induce immune tolerance and prevent autoimmunity. iNKT cells that differentially modulate adaptive immunity do not bear a unique phenotype and/or specific cytokine secretion profile, thus opening questions on how a single T cell subset can exert opposite immunological tasks. In this study, we show that iNKT cells perform their dual roles through a single mechanism of action relying on the cognate interaction with myeloid dendritic cells (DCs) and leading to opposite effects depending on the presence of other maturation stimuli simultaneously acting on DCs. The contact of murine purified iNKT cells with immature autologous DCs directly triggers the tolerogenic maturation of DCs, rendering them able to induce regulatory T cell differentiation and prevent autoimmune diabetes in vivo. Conversely, the interaction of the same purified iNKT cells with DCs, in the presence of simultaneous TLR4 stimulation, significantly enhances proinflammatory DC maturation and IL-12 secretion. The different iNKT cell effects are mediated through distinct mechanisms and activation of different molecular pathways within the DC: CD1d signaling and activation of the ERK1/2 pathway for the tolerogenic action, and CD40–CD40L interaction and NF-κB activation for the adjuvant effect. Our data suggest that the DC decision to undergo proinflammatory or tolerogenic maturation results from the integration of different signals received at the time of iNKT cell contact and could have important therapeutic implications for exploiting iNKT cell adjuvant/regulatory properties in autoimmune diseases, infections, and cancer.

Section: Discussionmentioning

confidence: 99%

On/Off TLR Signaling Decides Proinflammatory or Tolerogenic Dendritic Cell Maturation upon CD1d-Mediated Interaction with Invariant NKT Cells

Conforti-Andreoni

Pietro

Usuelli

et al. 2010

“…Indeed, IFN-␥ has been shown to up-regulate expression of TNF superfamily members on subsets of NK cells (54). CD8 T cell-secreted IL-2, TNF-␣, or direct T/NK cell contact could also contribute to NK cell activation (55,56). Activated DCs have been shown to trigger NK cells (57,58).…”

Section: Discussionmentioning

confidence: 99%

CD8 T Cell Help for Innate Antitumor Immunity

Shanker

Verdeil

Buferne

et al. 2007

Innate immunity is considered to initiate adaptive antitumor responses. We demonstrate that monoclonal CD8 T lymphocytes reactive to tumor Ag P1A on P815 mastocytoma cells provide essential “help” to NK cells for rejection of P1A-deficient tumors. RAG-deficient mice have normal NK cells but do not reject either tumor. Reconstitution of these mice with P1A-specific T cells conferred resistance to both P1A-expressing and -deficient tumor cells provided they were present at the same site. Elimination of Ag-negative tumor variants required both activated T and NK cells. Gene expression profiling of NK cells infiltrating P1A-positive tumors in mice with specific CD8 T cells demonstrated an activated effector phenotype. However, CD8 T cell help to NK cells appeared ineffective for P1A-negative variants separated from the P1A-positive tumor. Local tumor Ag-specific T cell-NK cell collaboration results in the elimination of tumor cells whether they express or not the T cell tumor Ag epitope, thus containing the emergence of tumor escape variants before metastasis.

“…NK cells express transmembrane (tm) TNFR1 and tmTNFR2 (32). TNFR1 is known to be activated by tmTNF as well as by soluble TNF; however, TNFR2 can only be activated by tmTNF (33,34).…”

Section: Bmcmc-mediated Ifn-g Secretion By Nk Cells Is Tnf-a Independentmentioning

confidence: 99%

Lipopolysaccharide-Mediated Mast Cell Activation Induces IFN-γ Secretion by NK Cells

Vosskuhl

Greten

Manns

et al. 2010