Memory CD4+ T Cells Are Required for Optimal NK Cell Effector Functions against the Opportunistic Fungal Pathogen Pneumocystis murina

Abstract

Little is known about the role of NK cells or their interplay with other immune cells during opportunistic infections. Using our murine model of Pneumocystis pneumonia, we found that loss of NK cells during immunosuppression results in substantial Pneumocystis lung burden. During early infection of C57B/6 CD4+ T cell depleted mice, there were significantly less NK cells in the lung tissue compared to CD4+ T cell intact animals, and the NK cells present demonstrated decreased upregulation of the activation marker NKp46 and production of the effector cytokine, IFN-γ. Furthermore, co-incubation studies revealed a significant increase in fungal killing when NK cells were combined with CD4+ T cells compared to either cell alone which was coincident with a significant increase in perforin production by NK cells. Finally, however, we found through adoptive transfer that memory CD4+ T cells are required for significant NK cell upregulation of the activation marker NKG2D and production of IFN-γ, granzyme B and perforin during Pneumocystis infection. To the best of our knowledge, this study is the first to not only demonstrate a role for NK cells in immunity to Pneumocystis pneumonia, but also to establish a functional relationship between CD4+ T cells and NK cells in the host response to an opportunistic fungal pathogen.

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…”

Novel Pneumocystis Antigen Discovery Using Fungal Surface Proteomics

“…We propagated and harvested high-yield P. murina from Rag2 Ϫ/Ϫ Il2rg Ϫ/Ϫ mice (10). The surface proteins of purified P. murina were biotin labeled and analyzed using LC-MS to determine peptide sequences and sites of N-hydroxysuccinimide (NHS) ester labeling.…”

CD4 + T-Cell Help Enhances NK Cell Function following Therapeutic HIV-1 Vaccination

“…ecent studies in mice and nonhuman primates have reported that antigen-specific CD4 ϩ T cells can provide immunological help not only to CD8 ϩ T cells and B cells but also to NK cells (1,2). In humans, the potential of T cell-derived interleukin-2 (IL-2) to enhance NK cell activation has been suggested in vitro in response to influenza virus (3) and to Plasmodium falciparum infections (4) and in vivo in subjects receiving rabies virus vaccination (5) or exposed to malaria (6,7).…”