Granzyme A Produced by g9d2 T Cells Induces Human Macrophages to Inhibit Growth of an Intracellular Pathogen
A small subset of human T cells express γ9δ2 T cell receptors and recognize unique non-peptide phosphoantigens expressed by microbes and damaged cells, such as cancer. These cells are important because: 1) they reside within skin and mucosal surfaces at critical points of initial pathogen invasion, and 2) they are not restricted by polymorphic HLA types and thus can be activated by the same cognate antigens in highly diverse populations. Many important human pathogens such as the causes of AIDS, malaria, tuberculosis and others induce potent responses in γ9δ2 T cells that can be protective. However, the key mechanisms involved in γ9δ2 T cell-mediated protective immunity are not well defined. We have found that γ9δ2 T cells produce soluble granzyme A which correlates with their ability to protect against intracellular mycobacterial growth. We show directly that highly purified granzyme A alone can trigger human monocytes to control intracellular mycobacteria. We further show that the granzyme A-induced mycobacterial inhibition required production of TNF-α by infected monocytes. These studies may have important implications for future vaccine development and novel therapeutic strategies.