Protective antifungal memory CD8+ T cells are maintained in the absence of CD4+ T cell help and cognate antigen in mice
Som G. Nanjappa, … , Thomas Sullivan, Bruce Klein
Som G. Nanjappa, … , Thomas Sullivan, Bruce Klein
Published February 22, 2012
Citation Information: J Clin Invest. 2012;122(3):987-999. https://doi.org/10.1172/JCI58762.
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Protective antifungal memory CD8+ T cells are maintained in the absence of CD4+ T cell help and cognate antigen in mice

Abstract

Individuals who are immunocompromised, including AIDS patients with few CD4+ T cells, are at increased risk for opportunistic fungal infections. The incidence of such infections is increasing worldwide, meaning that the need for antifungal vaccines is increasing. Although CD4+ T cells play a dominant role in resistance to many pathogenic fungal infections, we have previously shown that vaccination can induce protective antifungal CD8+ T cell immunity in the absence of CD4+ T cells. However, it has not been determined whether vaccine-induced antifungal CD8+ T cell memory can be maintained in the absence of CD4+ T cell help. Here, we have shown in a mouse model of vaccination against blastomycosis that antifungal memory CD8+ T cells are maintained in the absence of CD4+ T cells without loss of numbers or function for at least 6 months and that the cells protect against infection. Using a system that enabled us to induce and track antigen-specific, antifungal CD8+ T cells, we found that such cells were maintained for at least 5 months upon transfer into naive mice lacking both CD4+ T cells and persistent fungal antigen. Additionally, fungal vaccination induced a profile of transcription factors functionally linked with persistent memory in CD8+ T cells. Thus, unlike bacteria and viruses, fungi elicit long-term CD8+ T cell memory that is maintained without CD4+ T cell help or persistent antigen. This has implications for the development of novel antifungal vaccine strategies effective in immunocompromised patients.

Authors

Som G. Nanjappa, Erika Heninger, Marcel Wüthrich, Thomas Sullivan, Bruce Klein

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Figure 4

Antigen-specific antifungal CD8+ T cell responses to SIINFEKL-expressing vaccine yeast.

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Antigen-specific antifungal CD8+ T cell responses to SIINFEKL-expressing...
(A) Schematic diagram illustrating generation of recombinant yeast carrying the OT-I epitope SIINFEKL fused to truncated BAD-1 and fluorescent mCherry. N-term, N terminus; C-term, C terminus. (B) Microscopic visualization of recombinant vaccine yeast. Surface localization of model epitope-mCherry fusion (white arrow). Original magnification, ×60. (C and D) Primary response of OT-I cells after vaccination. Approximately 1 × 106 Thy1.1+ OT-I cells were adoptively transferred to naive Thy1.2 mice. A day later, mice were vaccinated s.c. with SIINFEKL yeast (106 CFU). After 14 days, DLN cells were harvested and incubated at 37°C with SIINFEKL peptide or anti-CD3 and anti-CD28 antibodies for 5 hours. Cells were then surface stained with anti-Thy1.1, anti-CD8, and anti-CD44 before staining for intracellular cytokines with anti–IFN-γ and anti–TNF-α antibodies. The percentage of activated (CD44hi) and cytokine-producing OT-I T cells and polyclonal T cells was enumerated by flow cytometry (C). DLN cells were also directly surface stained using anti-CD8, anti-Thy1.1, anti-CD44, anti-CD62L, anti-CD127, anti–KLRG-1, anti-CD43, and anti-CD27 antibodies and analyzed by flow cytometry (D). Numbers in dot plots indicate the percentage of cells gated on activated (CD44hi) OT-I and polyclonal T cells. Plots are representative of data collected from 4 mice per group.