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Updated: May 16, 2026

Whole Blood Assay with Dual Co-Stimulation for Antigen-Specific Analysis of Host Immunity to Fungal and Viral Pathogens
Published on: September 20, 2024
Memory CD4+ T cells are required for optimal NK cell effector functions against the opportunistic fungal pathogen
Michelle N Kelly1, Mingquan Zheng, Sanbao Ruan
1Section of Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA. mkelly3@lsuhsc.edu
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 fewer NK cells in the lung tissue compared with 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, coincubation studies revealed a significant increase in fungal killing when NK cells were combined with CD4(+) T cells compared with 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 NK group 2D and production of IFN-γ, granzyme B, and perforin during Pneumocystis infection. To the best of our knowledge, this study is the first to demonstrate a role for NK cells in immunity to Pneumocystis pneumonia, as well as to establish a functional relationship between CD4(+) T cells and NK cells in the host response to an opportunistic fungal pathogen.
Insights
Natural killer (NK) cells are crucial for controlling Pneumocystis pneumonia, an opportunistic infection. Their function is enhanced by CD4(+) T cells, highlighting a key immune interplay.
Area of Science:
- Immunology
- Infectious Diseases
Background:
- The role of natural killer (NK) cells in opportunistic infections remains poorly understood.
- Pneumocystis pneumonia (PCP) is a significant opportunistic infection, particularly in immunocompromised individuals.
Purpose of the Study:
- To investigate the role of NK cells in host defense against Pneumocystis pneumonia.
- To elucidate the interplay between NK cells and CD4(+) T cells during PCP.
Main Methods:
- Murine model of Pneumocystis pneumonia.
- CD4(+) T cell depletion and adoptive transfer experiments.
- Flow cytometry to assess NK cell activation markers (NKp46, NKGD) and cytokine production (IFN-γ, granzyme B, perforin).
Main Results:
- Loss of NK cells during immunosuppression led to increased Pneumocystis lung burden.
- Fewer and less activated NK cells were observed in CD4(+) T cell-depleted mice during early infection.
- Combined NK cells and CD4(+) T cells demonstrated enhanced fungal killing and perforin production compared to either cell type alone.
- Memory CD4(+) T cells were essential for NK cell activation and effector function during Pneumocystis infection.
Conclusions:
- NK cells play a vital role in controlling Pneumocystis pneumonia.
- CD4(+) T cells enhance NK cell activation and effector functions, including cytokine and cytotoxic molecule production.
- This study establishes a functional relationship between CD4(+) T cells and NK cells in the context of opportunistic fungal infections.
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