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

Yoshiro Yamashita,Koya Ariyoshi,Ikkoh Yasuda,Mayuko Osada-Oka,Toshiyuki Oe,Yasuko Tsunetsugu-Yokota,Takeshi Tanaka,Sohkichi Matsumoto,Yuriko Ozeki,Kenji Kawakami,Tansy Edwards,Kazutaka Terahara

doi:10.3389/fimmu.2019.02807

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 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 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.

Highlights

One-quarter of the world’s population harbors Mycobacterium tuberculosis (M. tuberculosis) [1], a majority of them are asymptomatic with the pathogen remaining dormant resulting in a latent M. tuberculosis infection (LTBI)
We demonstrate that the level of Th1 cytokines, such as IFN-γ, IL-2, and TNF-α responses were dominant after TB onset regardless of the type of antigen
This is the first study comprehensibly demonstrating the activation of nonTh1 cytokines by latency-associated antigens in comparison to ESAT-6/CFP-10 before TB onset and after TB treatment

Summary

Introduction

One-quarter of the world’s population harbors Mycobacterium tuberculosis (M. tuberculosis) [1], a majority of them are asymptomatic with the pathogen remaining dormant resulting in a latent M. tuberculosis infection (LTBI). Chronic nature of infection delays the patients from seeking adequate and timely health care [3]. This time lag between the gradual onset of TB to the time of diagnosis and initiating treatment prolongs the critical period during with the patients are being infectious and spreading aerosolic M. tuberculosis. In the past two decades, IFN-γ release assays (IGRAs) have been developed and are widely utilized in clinical settings [4] This system quantifies the IFN-γ response to M. tuberculosis-specific antigens, which are expressed during active state, such as ESAT-6 and CFP-10, and detects the M. tuberculosis infection with a higher specificity than Mantoux skin test. The predictive value for the development of TB from LTBI remains

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