Diminished TLR2-TLR9 mediated CD4+ T cell responses are associated with increased inflammation in intraocular tuberculosis

Ravi Kumar Sharma,Naresh Sachdeva,Amod Gupta,Zafar K Khan,Vishali Gupta,Reema Bansal,Ajinkya Pattekar,Kusum Sharma,Ashutosh Nath Aggarwal,Jyoti Sharma

doi:10.1038/s41598-018-32234-3

Abstract

Intraocular tuberculosis (IOTB) is amongst the leading causes of uveitis in tropical countries. Despite reports on involvement of proinflammatory cytokines, studies on innate immune responses in disease pathogenesis are lacking. Reports from animal models and patients with pulmonary tuberculosis indicate that defects in toll like receptor (TLR)2 and TLR9 signalling predispose them to tuberculosis. In this context, we investigated the role of TLR2, TLR4 and TLR9 in generation of CD4+ T effector (Teff) cell responses during IOTB. Firstly, the cells in vitreous fluids showed lower expression of TLR2 and TLR9 in IOTB as compared to non-uveitis and non-TB uveitis groups. Next, peripheral CD4+ Teff cells of subjects with IOTB showed decreased proliferative responses and lower induction of Tregs following TLR2 and TLR9 stimulation. Further, TLR9 ligation resulted in increased IFN-γ and IL-17a but decreased expression of IL-10 and TGF-β. Lastly, lower expression of genes involved in TLR9 signalling after direct TLR9 ligation was observed in IOTB. Collectively, our results show that a subdued response to direct TLR2 and TLR9 stimulation in CD4+ T cells is associated with increased proinflammatory responses in IOTB. These findings reveal an important link between innate immune signalling and ensuing adaptive immune responses in IOTB with implications in other forms of extrapulmonary tuberculosis.

Highlights

Intraocular tuberculosis (IOTB) or tubercular uveitis is one of the leading causes of uveitis in tropical countries, including India and China[1,2]
We provided evidence that IOTB involves a subdued response to TLR2 and TLR9 stimulation and in particular, direct TLR9 signalling in CD4+ T effector (Teff) cells, which manifests into lower Treg induction and elevated proinflammatory responses
As key toll like receptor (TLR) responding to Mycobacterium tuberculosis, we assessed the expression of TLR2, TLR4 and TLR9 in cells of vitreous humor in IOTB

Summary

Introduction

Intraocular tuberculosis (IOTB) or tubercular uveitis is one of the leading causes of uveitis in tropical countries, including India and China[1,2]. The only indicative evidence of the presence of a foreign TLR ligand in the eye is mycobacterial DNA, a TLR9 ligand, as shown by our group and others[6,12] In this context, we recently observed that T cells form a major proportion of ocular infiltrating cells in IOTB and these infiltrated CD4+ T cells show lower uptake of TLR9 ligand, ODN 2216, than the peripheral CD4+ T cells[13]. We provided evidence that IOTB involves a subdued response to TLR2 and TLR9 stimulation and in particular, direct TLR9 signalling in CD4+ Teff cells, which manifests into lower Treg induction and elevated proinflammatory responses. We could further demonstrate association between TLR2 and TLR9 mediated CD4+ Teff cell function and ocular inflammation in IOTB

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Conclusion