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CD4+ T cells from HIV-1 patients with impaired Th1 effector responses to Mycobacterium tuberculosis exhibit diminished histone and nucleoprotein signatures.

ABSTRACT: HIV+ patients have an increased risk for tuberculosis disease despite clinical management with ARTs. We established a culture model of Mtb-infection in PBMCs from HIV+ PPD+ donors on suppressive ART (median 6.4years) with negligible viral loads (median<50copies/mL) and stable CD4+ T cell counts (517cells/mm^3). We observed that HIV+ patient lymphocytes harbored a recruitment defect to Mtb-infected monocytes. To investigate these immune defects on a per cell basis, purified CD4+ T cells from HIV patients were assessed by label-free quantification protein mass spectrometry. CD4+ T cells from HIV patients displayed diminished nucleoprotein levels - notably of histone variant H2a.Z and ribonucleoprotein A1. Only within healthy donors, transcriptional regulatory histone variant H2a.Z expression was correlated to the extent of IFN-? induction upon Mtb-infection. Our findings may explain why HIV patients exhibit prolonged immune cell dysfunction despite suppressive ART, and implicate a per cell defect of CD4+ T cells.

SUBMITTER: Seu L

PROVIDER: S-EPMC5593129 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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CD4+ T cells from HIV-1 patients with impaired Th1 effector responses to Mycobacterium tuberculosis exhibit diminished histone and nucleoprotein signatures.

Seu Lillian L Mobley James A JA Goepfert Paul A PA

Clinical immunology (Orlando, Fla.) 20170525

HIV+ patients have an increased risk for tuberculosis disease despite clinical management with ARTs. We established a culture model of Mtb-infection in PBMCs from HIV+ PPD+ donors on suppressive ART (median 6.4years) with negligible viral loads (median<50copies/mL) and stable CD4+ T cell counts (517cells/mm^3). We observed that HIV+ patient lymphocytes harbored a recruitment defect to Mtb-infected monocytes. To investigate these immune defects on a per cell basis, purified CD4+ T cells from HIV ...[more]

PMID: 28552470

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Project description:Two billion people worldwide are estimated to be latently infected with Mycobacterium tuberculosis (Mtb) and are at risk for developing active tuberculosis since Mtb can reactivate to cause TB disease in immune-compromised hosts. Individuals with latent Mtb infection (LTBI) and BCG-vaccinated individuals who are uninfected with Mtb, harbor antigen-specific memory CD4(+) T cells. However, the differences between long-lived memory CD4(+) T cells induced by latent Mtb infection (LTBI) versus BCG vaccination are unclear. In this study, we characterized the immune phenotype and functionality of antigen-specific memory CD4(+) T cells in healthy BCG-vaccinated individuals who were either infected (LTBI) or uninfected (BCG) with Mtb. Individuals were classified into LTBI and BCG groups based on IFN-? ELISPOT using cell wall antigens and ESAT-6/CFP-10 peptides. We show that LTBI individuals harbored high frequencies of late-stage differentiated (CD45RA(-)CD27(-)) antigen-specific effector memory CD4(+) T cells that expressed PD-1. In contrast, BCG individuals had primarily early-stage (CD45RA(-)CD27(+)) cells with low PD-1 expression. CD27(+) and CD27(-) as well as PD-1(+) and PD-1(-) antigen-specific subsets were polyfunctional, suggesting that loss of CD27 expression and up-regulation of PD-1 did not compromise their capacity to produce IFN-?, TNF-? and IL-2. PD-1 was preferentially expressed on CD27(-) antigen-specific CD4(+) T cells, indicating that PD-1 is associated with the stage of differentiation. Using statistical models, we determined that CD27 and PD-1 predicted LTBI versus BCG status in healthy individuals and distinguished LTBI individuals from those who had clinically resolved Mtb infection after anti-tuberculosis treatment. This study shows that CD4(+) memory responses induced by latent Mtb infection, BCG vaccination and clinically resolved Mtb infection are immunologically distinct. Our data suggest that differentiation into CD27(-)PD-1(+) subsets in LTBI is driven by Mtb antigenic stimulation in vivo and that CD27 and PD-1 have the potential to improve our ability to evaluate true LTBI status.

Project description: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 IFN?+ 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.

Dataset Information

CD4+ T cells from HIV-1 patients with impaired Th1 effector responses to Mycobacterium tuberculosis exhibit diminished histone and nucleoprotein signatures.

Publications

CD4+ T cells from HIV-1 patients with impaired Th1 effector responses to Mycobacterium tuberculosis exhibit diminished histone and nucleoprotein signatures.

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