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.
View: Text | PDF
Research Article Immunology

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

×

Figure 7

Antifungal IFN-γ+ CD8+ T cells preferentially express CXCR3, which is required for recruitment into lungs, but is independent of CD4+ T cell help.

Options: View larger image (or click on image) Download as PowerPoint
Antifungal IFN-γ+ CD8+ T cells preferentially express CXCR3, which is re...
(A) Expression of CXCR3. Naive 7- to 8-week-old mice with CD4+ T cell depletion were vaccinated. Cells from DLNs (A) and lungs (B) were collected and restimulated ex vivo using anti-CD3 and anti-CD28 for 5 hours. Cells were surface stained with anti-CD8, anti-CD44, and anti-CXCR3 antibodies and permeabilized to stain intracellular IFN-γ, TNF-α, and IL-17A. The percentage of cytokine-producing CD8+ T cells that expressed CXCR3 was quantitated by flow cytometry. For CXCR3-blocking experiments (C), 100 μg of LEAF purified hamster anti-mouse CXCR3 was given i.v. at days 0, +1, and +2 after challenge. On day 4 after challenge, lungs were harvested to enumerate the number of cytokine-producing CD8+ T cells by flow cytometry. Each symbol represents 1 mouse. n = 5 mice/group. Data are representative of 2 independent experiments. ***P < 0.001.