Abstract
T-cell-mediated immune responses play a fundamental role in controlling Mycobacterium tuberculosis (M. tuberculosis) infection, and traditionally, this response is thought to be mediated by Th1-type CD4+ T-cells secreting IFN-γ. While studying the function and specificity of M. tuberculosis-reactive CD4+ T-cells in more detail at the single cell level; however, we found a human CD4+ T-cell population with a naive phenotype that interestingly was capable of producing multiple cytokines (TCNP cells). CD4+ TCNP cells phenotyped as CD95lo CD28int CD49dhi CXCR3hi and showed a broad distribution of T cell receptor Vβ segments. They rapidly secreted multiple cytokines in response to different M. tuberculosis antigens, their frequency was increased during active disease, but was comparable to latent tuberculosis infection in treated TB patients. These results identify a novel human CD4+ T-cell subset involved in the human immune response to mycobacteria, which is present in active TB patients’ blood. These results significantly expand our understanding of the immune response in infectious diseases.
Highlights
Several studies in experimental mouse models and in HIV-infected patients have underscored the essential role of CD4+ T-cells and Th1 immunity in protection against tuberculosis (TB) [1]
Peripheral blood mononuclear cells from patients with active TB disease, were stimulated for 6 h with a pool of peptides spanning the whole sequences of M. tuberculosis ESAT-6 and CFP-10 antigens and assessed for intracellular interferon-γ (IFN-γ)
Surprisingly, a sizeable yet variable fraction (5–24%) of CD4+ T-cells responding to ESAT6/CFP-10 in patients with active TB disease had a naive (TN, CD45RA+CCR7+) membrane expression phenotype
Summary
Several studies in experimental mouse models and in HIV-infected patients have underscored the essential role of CD4+ T-cells and Th1 immunity in protection against tuberculosis (TB) [1]. Protective immune responses against mycobacterial infection are thought to be dependent on quality, as measured by the capacity of T cells to exert multiple. Detection of antigen-specific cytokine production in indivi dual T cells by intracellular cytokine staining and flow cytometry has been widely used to identify specific subsets of T cells producing different types of cytokines and to correlate their cytokine production patterns with functional phenotypes according to the expression of surface markers. In several infection models, including TB, TEM cells are expanded during active bacillary replication, while TCM cells are mostly detectable after control and eradication of infection [4, 8], indicating that distinct memory phenotypes and functions are associated with different stages of infection
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