Research Article: Circulating HLA-DR+CD4+ effector memory T cells resistant to CCR5 and PD-L1 mediated suppression compromise regulatory T cell function in tuberculosis

Date Published: September 19, 2018

Publisher: Public Library of Science

Author(s): Asma Ahmed, Vasista Adiga, Soumya Nayak, J. Anto Jesuraj Uday Kumar, Chirag Dhar, Pravat Nalini Sahoo, Bharath K. Sundararaj, George D. Souza, Annapurna Vyakarnam, David M. Lewinsohn.


Chronic T cell activation is a hallmark of pulmonary tuberculosis (PTB). The mechanisms underpinning this important phenomenon are however, poorly elucidated, though known to rely on control of T effector cells (Teff) by regulatory T cells (Treg). Our studies show that circulating natural Treg cells in adults with PTB preserve their suppressive potential but Teff cells from such subjects are resistant to Treg-mediated suppression. We found this to be due to expansion of an activated Teff subset identified by Human Leukocyte Antigen (HLA)-DR expression. Sensitivity to suppression was restored to control levels by depletion of this subset. Comparative transcriptome analysis of Teff cells that contain HLA-DR+ cells versus the fraction depleted of this population identified putative resistance mechanisms linked to IFNG, IL17A, IL22, PD-L1 and β-chemokines CCL3L3, CCL4 expression. Antibody blocking experiments confirmed HLA-DR+ Teff cells, but not the fraction depleted of HLA-DR+ effectors, to be resistant to Treg suppression mediated via CCR5 and PD-L1 associated pathways. In the presence of HLA-DR+ Teff cells, activation of NFκB downstream of CCR5 and PD-L1 was perturbed. In addition, HLA-DR+ Teff cells expressed significantly higher levels of Th1/Th17 cytokines that may regulate Treg function through a reciprocal counter-balancing relationship. Taken together, our study provides novel insight on how activated HLA-DR+CD4+ T cells may contribute to disease associated inflammation by compromising Treg-mediated suppression in PTB.

Partial Text

TB is a complex disease which claims several lives annually. In 2016, 1.3 million human immunodeficiency virus (HIV) negative (-ve) and 374,000 HIV positive (+ve) people succumbed to TB [1]. The spread of TB and mortality associated with it has been aggravated by the alarming rise in multidrug resistant (MDR) and extensively drug resistant (XDR) cases. Control of TB is further challenged by the availability of just one preventive vaccine, BCG, which when given at birth confers good protection in children but does not efficiently prevent new infection and reactivation of latent TB in adults [2]. India has the highest burden of TB and MDR TB globally. In 2016, about 2.8 million people were afflicted with TB in India, of which about 0.43 million died [3]. These statistics call for a better understanding of disease processes in Mycobacterium tuberculosis (Mtb) infection.

Data presented in this study provides fresh insight into dysregulation of Treg mediated homeostasis and the possible mechanisms underpinning this in active PTB. Novel aspects of the study are (a) loss of Treg-mediated function in TB is due to Teff cells becoming resistant to Treg mediated suppression rather than inability of Treg cells to suppress Teff cells or a drop in circulating Treg cell frequency (b) this resistance is due to expansion of a small population of HLA-DR+ CD4+ Teff cells as depletion of this fraction restores suppression to control levels, and (c) that a combination of mechanisms accounts for the resistance of total HLA-DR+ Teff cells to suppression by Treg cells, which includes expression of high levels of IFNγ, IL-17A and IL-22, known to counter-regulate Treg cell function [38, 39, 54]. Additionally, HLA-DR+CD4+ Teff cells possibly interfere with PD-L1 and CCR5 mediated Treg-suppression, as depleting the HLA-DR+ fraction restores sensitivity of Teff cells to suppression via these pathways.