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

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.

Author Summary

Mycobacterium tuberculosis (Mtb) is an inhaled pathogen that primarily infects the lungs and causes the disease, tuberculosis. Recent WHO statistics show that more than 2 billion people are infected with Mtb, of these over 1 million people die every year. Researchers over the last several decades have tried to determine how our immune system fights Mtb infection. It is known that CD4 T cells, and the pro-inflammatory cytokine, IFNγ, are required to control Mtb infection in humans and in mice. Based on these observations, it is commonly assumed that vaccines that maximize IFNγ-producing Mtb-specific CD4 T cell numbers will be the most effective. For the first time, we tested this idea directly and our results led us to the unexpected finding that Mtb specific CD4 T cells do not require IFNγ in order to protect mice from Mtb infection. Our results challenge the model that optimization of IFNγ-producing CD4 T cells will optimize vaccine induced protection against M. tuberculosis .