Induced recruitment of NK cells to lymph nodes provides IFN-γ for TH1 priming

Naive T cells are stimulated by antigen-presenting dendritic cells (DCs) in secondary lymphoid organs, but whether other types of cell participate in T cell priming is unclear. Here we show in mice that natural killer (NK) cells, which are normally excluded from lymph nodes, are rapidly recruited in a CCR7-independent, CXCR3-dependent manner to lymph nodes on stimulation by the injection of mature DCs. Recruitment of NK cells is also induced by some, but not all, adjuvants and correlates with the induction of T helper cell type 1 (TH1) responses. NK cell depletion and reconstitution experiments show that NK cells provide an early source of interferon-γ (IFN-γ) that is necessary for TH1 polarization. Taken together, our results identify an induced pathway of NK cell migration in antigen-stimulated lymph nodes and a mechanism by which some adjuvants may facilitate TH1 responses.

[1]  R. Biassoni,et al.  Human natural killer cells: their origin, receptors and function , 2002, European journal of immunology.

[2]  A. Moretta.  Natural killer cells and dendritic cells: rendezvous in abused tissues , 2002, Nature Reviews Immunology.

[3]  N. Elshourbagy,et al.  Characterization of CC‐chemokine receptor 7 expression on murine T cells in lymphoid tissues , 2003, Immunology.

[4]  Diego Piccioli,et al.  Contact-dependent Stimulation and Inhibition of Dendritic Cells by Natural Killer Cells , 2002, The Journal of experimental medicine.

[5]  J. Cyster,et al.  Chemokine Requirements for B Cell Entry to Lymph Nodes and Peyer's Patches , 2002, The Journal of experimental medicine.

[6]  Polly Matzinger,et al.  'Educated' dendritic cells act as messengers from memory to naive T helper cells , 2004, Nature Immunology.

[7]  W. Yokoyama,et al.  The dynamic life of natural killer cells. , 2004, Annual review of immunology.

[8]  P. Scott,et al.  Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice , 1993, The Journal of experimental medicine.

[9]  Richard A Flavell,et al.  Instruction of Distinct CD4 T Helper Cell Fates by Different Notch Ligands on Antigen-Presenting Cells , 2004, Cell.

[10]  W. Hancock,et al.  Requirement of the Chemokine Receptor CXCR3 for Acute Allograft Rejection , 2000, The Journal of experimental medicine.

[11]  P. Moingeon,et al.  Towards the rational design of Th1 adjuvants. , 2001, Vaccine.

[12]  Jianfei Yang,et al.  T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells , 2002, Nature Immunology.

[13]  S. Szabo,et al.  Molecular mechanisms regulating Th1 immune responses. , 2003, Annual review of immunology.

[14]  Dolca Thomas,et al.  The Abundant NK Cells in Human Secondary Lymphoid Tissues Require Activation to Express Killer Cell Ig-Like Receptors and Become Cytolytic1 , 2004, The Journal of Immunology.

[15]  R. Locksley,et al.  Interferon γ Derived from CD4+ T Cells Is Sufficient to Mediate T Helper Cell Type 1 Development , 1998, The Journal of experimental medicine.

[16]  P. Morel,et al.  Dendritic Cells Mediate NK Cell Help for Th1 and CTL Responses: Two-Signal Requirement for the Induction of NK Cell Helper Function 1 , 2003, The Journal of Immunology.

[17]  Kenneth M. Murphy,et al.  Dendritic cell regulation of TH1-TH2 development , 2000, Nature Immunology.

[18]  F. Sallusto,et al.  Dynamics of T lymphocyte responses: intermediates, effectors, and memory cells. , 2000, Science.

[19]  A. Diefenbach,et al.  Innate immune recognition by stimulatory immunoreceptors. , 2003, Current opinion in immunology.

[20]  J. Sedat,et al.  Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. , 2001, Immunity.

[21]  W. Paul,et al.  Conventional, Naive CD4+ T Cells Provide an Initial Source of IL-4 During Th2 Differentiation , 2000, The Journal of Immunology.

[22]  Adelheid Cerwenka,et al.  Natural killer cells, viruses and cancer , 2001, Nature Reviews Immunology.

[23]  U. V. von Andrian,et al.  Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. , 2004, Annual review of immunology.

[24]  Antonio Lanzavecchia,et al.  Central memory and effector memory T cell subsets: function, generation, and maintenance. , 2004, Annual review of immunology.

[25]  A. Lanzavecchia,et al.  Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation , 1996, The Journal of experimental medicine.

[26]  C. Janeway,et al.  Innate immune induction of the adaptive immune response. , 1999, Cold Spring Harbor symposia on quantitative biology.

[27]  Kouji Matsushima,et al.  Pivotal Role of Dendritic Cell–derived CXCL10 in the Retention of T Helper Cell 1 Lymphocytes in Secondary Lymph Nodes , 2002, The Journal of experimental medicine.

[28]  L. Williams,et al.  Mice Lacking Expression of Secondary Lymphoid Organ Chemokine Have Defects in Lymphocyte Homing and Dendritic Cell Localization , 1999, The Journal of experimental medicine.

[29]  C. Hsieh,et al.  T cell genetic background determines default T helper phenotype development in vitro , 1995, The Journal of experimental medicine.

[30]  R. Homer,et al.  Regulation of pulmonary fibrosis by chemokine receptor CXCR3. , 2004, The Journal of clinical investigation.

[31]  Giovanni Melioli,et al.  Human Dendritic Cells Activate Resting Natural Killer (NK) Cells and Are Recognized via the NKp30 Receptor by Activated NK Cells , 2002, The Journal of experimental medicine.

[32]  E. Wolf,et al.  CCR7 Coordinates the Primary Immune Response by Establishing Functional Microenvironments in Secondary Lymphoid Organs , 1999, Cell.

[33]  G. Trinchieri,et al.  Interleukin-12 and the regulation of innate resistance and adaptive immunity , 2003, Nature Reviews Immunology.

[34]  M. Caligiuri,et al.  NK cell and DC interactions. , 2004, Trends in immunology.

[35]  U. V. von Andrian,et al.  CXCL12 Mediates CCR7-independent Homing of Central Memory Cells, But Not Naive T Cells, in Peripheral Lymph Nodes , 2004, The Journal of experimental medicine.

[36]  P. Kalinski,et al.  High-level IL-12 production by human dendritic cells requires two signals. , 1998, International immunology.

[37]  N. Valiante,et al.  Recent advances in the discovery and delivery of vaccine adjuvants , 2003, Nature Reviews Drug Discovery.

[38]  K. Matsushima,et al.  Evidence for recruitment of plasmacytoid dendritic cell precursors to inflamed lymph nodes through high endothelial venules. , 2004, International immunology.

[39]  J. Sedgwick,et al.  Tumor Necrosis Factor–dependent Segmental Control of MIG Expression by High Endothelial Venules in Inflamed Lymph Nodes Regulates Monocyte Recruitment , 2001, The Journal of experimental medicine.

[40]  R. Steinman,et al.  Dendritic cells and the control of immunity , 1998, Nature.

[41]  Ulrich H. von Andrian,et al.  Homing and cellular traffic in lymph nodes , 2003, Nature Reviews Immunology.

[42]  T. Junt,et al.  β cells are responsible for CXCR3-mediated T-cell infiltration in insulitis , 2002, Nature Medicine.

[43]  N. Pavelka,et al.  A Contribution of Mouse Dendritic Cell–Derived IL-2 for NK Cell Activation , 2004, The Journal of experimental medicine.

[44]  G. Trinchieri,et al.  Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. , 1995, Journal of immunology.

[45]  M. Caligiuri,et al.  CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity. , 2003, Blood.

[46]  Antonio Lanzavecchia,et al.  Regulation of Dendritic Cell Migration to the Draining Lymph Node , 2003, The Journal of experimental medicine.

[47]  G. Trinchieri,et al.  Reciprocal Activating Interaction between Natural Killer Cells and Dendritic Cells , 2002, The Journal of experimental medicine.

[48]  A. Thiel,et al.  The small subset of CD56brightCD16– natural killer cells is selectively responsible for both cell proliferation and interferon‐γ production upon interaction with dendritic cells , 2004, European journal of immunology.

[49]  A. Satoskar,et al.  Mice lacking NK cells develop an efficient Th1 response and control cutaneous Leishmania major infection. , 1999, Journal of immunology.

[50]  G. Schuler,et al.  An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. , 1999, Journal of immunological methods.