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CD4⁺ T Responses Other Than Th1 Type Are Preferentially Induced by Latency-Associated Antigens in the State of Latent Mycobacterium tuberculosis Infection.

ABSTRACT: Mycobacterium tuberculosis (M. tuberculosis) produces a diverse range of antigenic proteins in its dormant phase. The cytokine profiles of CD4⁺ T cell responses, especially subsets other than Th1 type (non-Th1 type), against these latency-associated M. tuberculosis antigens such as ?-crystallin (Acr), heparin-binding hemagglutinin (HBHA), and mycobacterial DNA-binding protein 1 (MDP-1) remain elusive in relation to the clinical stage of M. tuberculosis infection. In the present study, peripheral blood mononuclear cells (PBMCs) collected from different stages of M. tuberculosis-infected cases and control PBMCs were stimulated with these antigens and ESAT-6/CFP-10. Cytokine profiles of CD4⁺ T cells were evaluated by intracellular cytokine staining using multicolor flow cytometry. Our results demonstrate that Th1 cytokine responses were predominant after TB onset independent of the type of antigen stimulation. On the contrary, non-Th1 cytokine responses were preferentially induced by latency-associated M. tuberculosis antigens, specifically IL-10 response against Acr in latent M. tuberculosis infection. From these results, we surmise a shift in the CD4⁺ T cell response from mixed non-Th1 to Th1 dominant type during TB progression.

SUBMITTER: Yamashita Y

PROVIDER: S-EPMC6897369 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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CD4+ T Responses Other Than Th1 Type Are Preferentially Induced by Latency-Associated Antigens in the State of Latent Mycobacterium tuberculosis Infection.

Yamashita Yoshiro Y Oe Toshiyuki T Kawakami Kenji K Osada-Oka Mayuko M Ozeki Yuriko Y Terahara Kazutaka K Yasuda Ikkoh I Edwards Tansy T Tanaka Takeshi T Tsunetsugu-Yokota Yasuko Y Matsumoto Sohkichi S Ariyoshi Koya K

Frontiers in immunology 20191129

Mycobacterium tuberculosis (M. tuberculosis) produces a diverse range of antigenic proteins in its dormant phase. The cytokine profiles of CD4+ T cell responses, especially subsets other than Th1 type (non-Th1 type), against these latency-associated M. tuberculosis antigens such as α-crystallin (Acr), heparin-binding hemagglutinin (HBHA), and mycobacterial DNA-binding protein 1 (MDP-1) remain elusive in relation to the clinical stage of M. tuberculosis infe ...[more]

PMID: 31849981

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Project description:BackgroundRapid and effective discrimination between active tuberculosis (ATB) and latent tuberculosis infection (LTBI) remains a challenge. There is an urgent need for developing practical and affordable approaches targeting this issue.MethodsParticipants with ATB and LTBI were recruited at Tongji Hospital (Qiaokou cohort) and Sino-French New City Hospital (Caidian cohort) based on positive T-SPOT results from June 2020 to January 2021. The expression of activation markers including HLA-DR, CD38, CD69, and CD25 was examined on Mycobacterium tuberculosis (MTB)-specific CD4+ T cells defined by IFN-γ, TNF-α, and IL-2 expression upon MTB antigen stimulation.ResultsA total of 90 (40 ATB and 50 LTBI) and another 64 (29 ATB and 35 LTBI) subjects were recruited from the Qiaokou cohort and Caidian cohort, respectively. The expression patterns of Th1 cytokines including IFN-γ, TNF-α, and IL-2 upon MTB antigen stimulation could not differentiate ATB patients from LTBI individuals well. However, both HLA-DR and CD38 on MTB-specific cells showed discriminatory value in distinguishing between ATB patients and LTBI individuals. As for developing a single candidate biomarker, HLA-DR had the advantage over CD38. Moreover, HLA-DR on TNF-α+ or IL-2+ cells had superiority over that on IFN-γ+ cells in differentiating ATB patients from LTBI individuals. Besides, HLA-DR on MTB-specific cells defined by multiple cytokine co-expression had a higher ability to discriminate patients with ATB from LTBI individuals than that of MTB-specific cells defined by one kind of cytokine expression. Specially, HLA-DR on TNF-α+IL-2+ cells produced an AUC of 0.901 (95% CI, 0.833-0.969), with a sensitivity of 93.75% (95% CI, 79.85-98.27%) and specificity of 72.97% (95% CI, 57.02-84.60%) as a threshold of 44% was used. Furthermore, the performance of HLA-DR on TNF-α+IL-2+ cells for differential diagnosis was obtained with validation cohort data: 90.91% (95% CI, 72.19-97.47%) sensitivity and 68.97% (95% CI, 50.77-82.73%) specificity.ConclusionsWe demonstrated that HLA-DR on MTB-specific cells was a potentially useful biomarker for accurate discrimination between ATB and LTBI.

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.

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CD4⁺ T Responses Other Than Th1 Type Are Preferentially Induced by Latency-Associated Antigens in the State of Latent Mycobacterium tuberculosis Infection.

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CD4<sup>+</sup> T Responses Other Than Th1 Type Are Preferentially Induced by Latency-Associated Antigens in the State of Latent <i>Mycobacterium tuberculosis</i> Infection.

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