A Gamma Interferon Independent Mechanism of CD4 T Cell Mediated Control of M. tuberculosis Infection in vivo

Alena M Gallegos,Miriam Samstein,Michael S Glickman,Jeroen W J Van Heijst,Xiaodi Su,Eric G Pamer,Lalita Ramakrishnan

doi:10.1371/journal.ppat.1002052

Abstract

CD4 T cell deficiency or defective IFNγ signaling render humans and mice highly susceptible to Mycobacterium tuberculosis (Mtb) infection. The prevailing model is that Th1 CD4 T cells produce IFNγ to activate bactericidal effector mechanisms of infected macrophages. Here we test this model by directly interrogating the effector functions of Th1 CD4 T cells required to control Mtb in vivo. While Th1 CD4 T cells specific for the Mtb antigen ESAT-6 restrict in vivo Mtb growth, this inhibition is independent of IFNγ or TNF and does not require the perforin or FAS effector pathways. Adoptive transfer of Th17 CD4 T cells specific for ESAT-6 partially inhibited Mtb growth while Th2 CD4 T cells were largely ineffective. These results imply a previously unrecognized IFNγ/TNF independent pathway that efficiently controls Mtb and suggest that optimization of this alternative effector function may provide new therapeutic avenues to combat Mtb through vaccination.

Highlights

IFNc is essential for defense against Mycobacterium tuberculosis (Mtb) infection, as revealed by experimental studies using knockout mice and the unusually severe mycobacterial infections in patients with defects in the IFNc or IL-12 signaling pathways [1,2,3,4]
It is known that CD4 T cells, and the pro-inflammatory cytokine, IFNc, are required to control Mtb infection in humans and in mice
We tested this idea directly and our results led us to the unexpected finding that Mtb specific CD4 T cells do not require IFNc in order to protect mice from Mtb infection

Summary

Introduction

IFNc is essential for defense against Mtb infection, as revealed by experimental studies using knockout mice and the unusually severe mycobacterial infections in patients with defects in the IFNc or IL-12 signaling pathways [1,2,3,4]. The role of CD4 T cells in defense against Mtb infection has been inferred from the increased reactivation of latent Mtb infections in CD4 T cell deficient patients following HIV infection and severe tuberculosis observed in CD4 T cell-deficient mice [3,5]. These clinical and experimental findings have led to a widely accepted model positing that the critical immunologic mechanism of anti-mycobacterial immunity involves CD4 T cells that secrete IFNc to activate bactericidal functions of Mtb-infected macrophages. M. tuberculosis ESAT6-E12A was fully virulent, but was not affected by Th1-differentiated C7 cells, whereas wild type M. tuberculosis titers were reduced by approximately 50 fold (Figure 1B and C)

Author Summary

Findings

Materials and Methods