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The host response of CD28-deficient mice to Pneumocystis infection
Christine M Rose1, Stephanie L Kimzey, Jonathan M Green
1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Abstract:
Pneumocystis infection leads to a life threatening pneumonia in susceptible individuals. While depletion or dysfunction of CD4+T cells is a key determinant of susceptibility to Pneumocystis, the host response that leads to resolution of infection or lung injury is less well understood. We had previously shown that mice deficient in the T cell costimulatory molecule CD28 are susceptible to infection with Pneumocystis. A detailed analysis revealed that they clear Pneumocystis with delayed kinetics. This is associated with an influx of naïve CD8+ T cells. Depletion of CD8+ T cells did not alter organism burden, suggesting these cells are not responsible for clearance. Analysis of the cytokine milieu demonstrated a consistent increase in mRNA for IL-10 and IFN-gamma in the CD28-deficient mice. These data suggest that CD28 function in important in the efficiency of the host response to Pneumocystis pneumonia.
Insights
Mice lacking CD28 signaling show delayed Pneumocystis pneumonia clearance. This involves CD8+ T cells but not organism burden, highlighting CD28
Area of Science:
- Immunology
- Infectious Diseases
- Pulmonology
Background:
- Pneumocystis pneumonia (PCP) is a severe lung infection in immunocompromised individuals, often linked to CD4+ T cell deficiency.
- The host immune mechanisms driving PCP resolution and lung repair remain incompletely understood.
- Previous studies indicated susceptibility to PCP in mice lacking the CD28 costimulatory molecule.
Purpose of the Study:
- To investigate the role of CD28 costimulation in the host immune response to Pneumocystis infection.
- To elucidate the kinetics of Pneumocystis clearance and the cellular and molecular responses in CD28-deficient mice.
Main Methods:
- Comparative analysis of Pneumocystis clearance in wild-type and CD28-deficient mice.
- Flow cytometry to assess immune cell populations, including naive CD8+ T cells.
- Quantitative PCR to measure cytokine mRNA expression (IL-10, IFN-gamma) in lung tissue.
Main Results:
- CD28-deficient mice exhibited delayed kinetics in clearing Pneumocystis.
- An increased influx of naive CD8+ T cells was observed in the lungs of CD28-deficient mice.
- Depletion of CD8+ T cells did not affect Pneumocystis burden, and elevated IL-10 and IFN-gamma mRNA levels were noted in CD28-deficient mice.
Conclusions:
- CD28 costimulation is crucial for efficient host response and timely resolution of Pneumocystis pneumonia.
- While CD8+ T cells infiltrate, they do not appear to mediate organism clearance in this model.
- The findings underscore the importance of CD28-mediated signaling in orchestrating protective immunity against Pneumocystis.
