Abstract
Mycobacterium tuberculosis (Mtb) is a serious public health concern, infecting a quarter of the world and leading to 10 million cases of tuberculosis (TB) disease and 1. 5 million deaths annually. An effective type 1 CD4 T cell (TH1) immune response is necessary to control Mtb infection and defining factors that modulate Mtb-specific TH1 immunity is important to better define immune correlates of protection in Mtb infection. Helminths stimulate type 2 (TH2) immune responses, which antagonize TH1 cells. As such, we sought to evaluate whether co-infection with the parasitic helminth Schistosoma mansoni (SM) modifies CD4 T cell lineage profiles in a cohort of HIV-uninfected adults in Kisumu, Kenya. Individuals were categorized into six groups by Mtb and SM infection status: healthy controls (HC), latent Mtb infection (LTBI) and active tuberculosis (TB), with or without concomitant SM infection. We utilized flow cytometry to evaluate the TH1/TH2 functional and phenotypic lineage state of total CD4 T cells, as well as CD4 T cells specific for the Mtb antigens CFP-10 and ESAT-6. Total CD4 T cell lineage profiles were similar between SM+ and SM− individuals in all Mtb infection groups. Furthermore, in both LTBI and TB groups, SM infection did not impair Mtb-specific TH1 cytokine production. In fact, SM+ LTBI individuals had higher frequencies of IFNγ+ Mtb-specific CD4 T cells than SM− LTBI individuals. Mtb-specific CD4 T cells were characterized by expression of both classical TH1 markers, CXCR3 and T-bet, and TH2 markers, CCR4, and GATA3. The expression of these markers was similar between SM+ and SM− individuals with LTBI. However, SM+ individuals with active TB had significantly higher frequencies of GATA3+ CCR4+ TH1 cytokine+ Mtb-specific CD4 T cells, compared with SM− TB individuals. Together, these data indicate that Mtb-specific TH1 cytokine production capacity is maintained in SM-infected individuals, and that Mtb-specific TH1 cytokine+ CD4 T cells can express both TH1 and TH2 markers. In high pathogen burden settings where co-infection is common and reoccurring, plasticity of antigen-specific CD4 T cell responses may be important in preserving Mtb-specific TH1 responses.
Highlights
Despite advances in care in the past decades, tuberculosis (TB) disease is currently the leading cause of death due a single infectious agent
Having established that Schistosoma mansoni (SM) infection does not impair the capacity of CD4 T cells to produce TH1 cytokines, nor does it skew CD4 T cells in general toward a TH2 phenotype, we evaluated the impact of SM on Mycobacterium tuberculosis (Mtb)-specific CD4 T cell responses in individuals with latent Mtb infection (LTBI)
We hypothesized that SM infection would modulate the TH1 vs. TH2 lineage profile of Mtb-specific CD4 T cell responses
Summary
Despite advances in care in the past decades, tuberculosis (TB) disease is currently the leading cause of death due a single infectious agent. In vitro studies of human PBMCs exposed to SM antigens have demonstrated skewing of Mtb-specific CD4 T cells from a TH1 to a TH2 response; human monocyte-derived macrophages exposed to the same antigens have produced contradictory results with one study showing enhanced control and another showing impaired control of Mtb replication in vitro [38, 39] It remains unclear what impact, if any, co-infection with SM has on Mtbspecific immune responses, in humans. In each group we examined CD4 T cells for the expression of cytokines, transcription factors, and chemokine receptors associated with TH1 and TH2 lineage commitment simultaneously This allowed us to evaluate CD4 T cell lineage using both phenotypic and functional readouts; we measured co-expression of these markers to determine the variability and plasticity of the Mtb-specific CD4 T cell repertoire in the setting of human Mtb and SM co-infection
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