Helminth Infections Coincident with Active Pulmonary Tuberculosis Inhibit Mono- and Multifunctional CD4+ and CD8+ T Cell Responses in a Process Dependent on IL-10

Abstract

Tissue invasive helminth infections and tuberculosis (TB) are co-endemic in many parts of the world and can trigger immune responses that might antagonize each other. We have previously shown that helminth infections modulate the Th1 and Th17 responses to mycobacterial-antigens in latent TB. To determine whether helminth infections modulate antigen-specific and non-specific immune responses in active pulmonary TB, we examined CD4+ and CD8+ T cell responses as well as the systemic (plasma) cytokine levels in individuals with pulmonary TB with or without two distinct helminth infections—Wuchereria bancrofti and Strongyloides stercoralis infection. By analyzing the frequencies of Th1 and Th17 CD4+ and CD8+ T cells and their component subsets (including multifunctional cells), we report a significant diminution in the mycobacterial–specific frequencies of mono- and multi–functional CD4+ Th1 and (to a lesser extent) Th17 cells when concomitant filarial or Strongyloides infection occurs. The impairment in CD4+ and CD8+ T cell cytokine responses was antigen-specific as polyclonal activated T cell frequencies were equivalent irrespective of helminth infection status. This diminution in T cell responses was also reflected in diminished circulating levels of Th1 (IFN-γ, TNF-α and IL-2)- and Th17 (IL-17A and IL-17F)-associated cytokines. Finally, we demonstrate that for the filarial co-infections at least, this diminished frequency of multifunctional CD4+ T cell responses was partially dependent on IL-10 as IL-10 blockade significantly increased the frequencies of CD4+ Th1 cells. Thus, co-existent helminth infection is associated with an IL-10 mediated (for filarial infection) profound inhibition of antigen-specific CD4+ T cell responses as well as protective systemic cytokine responses in active pulmonary TB.

Cytokines and Chemokines inMycobacterium tuberculosisInfection

“…In addition, increased accumulation of T REGS expressing IL-10 correlates with increased bacterial burden and more severe TB in an Indian population (343, 344) and a high level of IL-10 at the end of treatment in pulmonary TB patients is associated with TB recurrence (345). Finally, infection with helminths in TB patients results in decreased antigen-specific IFNγ and IL-17 responses, which is dependent on IL-10, as IL-10 blockade significantly increases frequencies of IFNγ producing cells (346, 347). …”

Helminth-Tuberculosis Co-infection: An Immunologic Perspective

“…For example, it has been shown that intestinal helminth co-infection is accompanied by lowered in vitro production of IFNγ and elevated production of IL-10 in individuals with active pulmonary tuberculosis [60]. Similarly, it was also recently shown that helminth infections with coincident active TB have marked decreases in dual-functional Th1 and Th17 cell frequencies [77] which, in one study at least, may be associated with increased Treg and Th2 responses [61]. …”

Mycobacterium tuberculosis‐specific CD4+ T‐cell response is increased, and Treg cells decreased, in anthelmintic‐treated patients with latent TB

“…In Indian patients with LTBI, coincident hookworm infection reduced Mtb-specific Th1 and Th17 CD4 T cells [14]. Indian pulmonary TB patients with Wucheria or Stronglyoides also showed reduced CD4 and CD8 T-cell responses to mycobacterial antigens, which could be partly blocked with anti-IL-10 neutralizing antibodies [27].…”

“…In Indian patients with LTBI, coincident hookworm infection reduced Mtb-specific Th1 and Th17 CD4 T cells [14]. Indian pulmonary TB patients with Wucheria or Stronglyoides also showed reduced CD4 and CD8 T-cell responses to mycobacterial antigens, which could be partly blocked with anti-IL-10 neutralizing antibodies [27].In this study, we measured the impact of anthelmintic treatment on the immune response to Mtb in LTBI in a migrant cohort in London. As United Kingdom is not a helminth endemic area, reinfection is not likely in this setting.…”