Primed Antigen-Specific CD4+ T Cells Are Required for NK Cell Activation In Vivo upon Leishmania major Infection

Abstract

The ability of NK cells to rapidly produce IFN-γ is an important innate mechanism of resistance to many pathogens including Leishmania major. Molecular and cellular components involved in NK cell activation in vivo are still poorly defined, although a central role for dendritic cells has been described. In this study, we demonstrate that Ag-specific CD4+ T cells are required to initiate NK cell activation early on in draining lymph nodes of L. major-infected mice. We show that early IFN-γ secretion by NK cells is controlled by IL-2 and IL-12 and is dependent on CD40/CD40L interaction. These findings suggest that newly primed Ag-specific CD4+ T cells could directly activate NK cells through the secretion of IL-2 but also indirectly through the regulation of IL-12 secretion by dendritic cells. Our results reveal an unappreciated role for Ag-specific CD4+ T cells in the initiation of NK cell activation in vivo upon L. major infection and demonstrate bidirectional regulations between innate and adaptive immunity.

Adoptively transferred natural killer cells maintain long-term antitumor activity by epigenetic imprinting and CD4+T cell help

“…22,24,25 Infection and tumor models in mice also showed that antigen-specific CD4 C T cells were required for the early IFNg induction from NK cells. 23,26,28 Our previous study revealed that CD4 C T cells were indispensable for maintaining potent effector function of adoptively transferred preactivated NK cells in total-body irradiated tumor-bearing mice. 9 To address whether CD4 C T cell help to NK cells can occur in absence of specific tumor antigens, tumor-derived factors and irradiation, we co-transferred CD4…”

“…9,[22][23][24][25][26][27][28] Regulatory T cells were reported to restrain IL-2 dependent CD4 C T cell help for NK cell proliferation and activity. [29][30][31] Our previous study demonstrated that adoptive transfer of IL-12/15/18-pretreated NK cells into irradiated tumor-bearing mice resulted in antitumor activity that required the presence of host CD4 C T cells and IL-2.…”

“…21 In addition, evidence emerged that NK cell-mediated immune responses also benefit from CD4 C T cell help. 9,[22][23][24][25][26][27][28] In certain infectious disease and tumor models, the cross-talk between CD4…”

Differential Requirements of Cellular and Humoral Immune Responses forFv2-Associated Resistance to Erythroleukemia and for Regulation of Retrovirus-Induced Myeloid Leukemia Development

“…In this regard, it is also noteworthy that the FV-specific priming and reactivation of CD4 ϩ T cells were not severely affected in B cell-deficient mice (27). Further, activation of both CD8 ϩ effecter T cells and NK cells upon pathogen invasion are known to depend on CD4 ϩ T cells, as CD4 ϩ T cells are required for the induction of CD8 ϩ effector cells (1,4,48,53) and NK cell activation upon pathogen infection is shown to be induced in the presence of CD4 ϩ effector T cells (6,22). In addition, CD4 ϩ T cells themselves may act as cytotoxic effector cells in eliminating FV-infected target cells (24).…”

Shaping of NK Cell Responses by the Tumor Microenvironment

“…Target cells initiate NK cell activation if they express sufficient amounts of ligands for activating NK cell receptors and low levels of ligands that engage inhibitory receptors [6]. In addition, NK cell priming with DCs [18], their interaction with CD4 + T cells ( [19] and our unpublished observations) or neutrophils [20,21] or the presence of certain cytokines, such as IL-2, IL-12, IL-15, IL-18 or IL-21 [22], can further enhance their effector function.…”