6-kDa Early Secreted Antigenic Target Protein (ESAT-6)

γδ T cells play an important role in innate immunity against infections. However, the regulation of these cells remains largely unknown. A recent report has shown that 6 kDa early secreted antigenic target (ESAT-6), an antigen of Mycobacterium tuberculosis, induces IFN-γ secretion by human γδ T cells. This discovery may help the exploration in this field.

Introduction of ESAT-6

Secreted proteins are among the most important molecules involved in host-pathogen interaction of Mycobacterium tuberculosis, the etiological agent of human tuberculosis (TB). Proteins containing typical signal sequences, such as the Ag85 T cell antigens get secreted by the Sec mediated secretory pathway, and secretion of other proteins may occur via the alternative Sec2 pathway or the twin-arginine translocation (TAT) system. However, the culture filtrate of M. tuberculosis also contains many small, highly immunogenic proteins that lack classical signal sequences. The ESAT-6 is the prototype of these proteins, which are characterized by the amino acid (aa) motif TrpXaa-Gly (WXG), and a size of approximately 100 aa. Multi-genome analyses predict the presence of WXG-100 proteins in a wide range of actinobacteria and Gram-positive bacteria, where they are thought to be secreted via novel secretion systems that were named ESAT-6 systems (ESX-1-ESX-5), or more recently type VII secretion systems (T7S system). In mycobacteria, these clusters typically also encode PE and PPE proteins characterized by their N-terminal motifs proline glutamic acid (PE) and proline-proline-glutamic acid (PPE).

Relationship of ESAT-6 and γδ T Cells

ESAT-6, an antigen of Mycobacterium tuberculosis, induces IFN-γ secretion by human γδ T cells. In addition, ESAT-6 also induces the activation and proliferation of γδ T cells. Phenotypic analysis indicates that IFN-γ producing γδ T cells are mainly effector memory cells with the surface phenotype of CD45RA^- CD62L^- CCR7^-. These results were further confirmed by the fact that naive γδ T cells from cord blood did not produce IFN-γ in response to ESAT-6. Further studies indicated that stimulation with ESAT-6 directly induced purified γδ T cells to produce IFN-γ, independent of both antigen-presenting cells and CD4⁺ T cells. Unexpectedly, depletion of CD4⁺ T cells markedly enhanced IFN-γ production by γδ T cells, indicating that CD4⁺ T cells regulate the response of γδ T cells. Importantly, CD4⁺CD25⁺ T regulatory (Treg) cells but not CD4⁺CD25- T cells significantly inhibited IFN-γ production by γδ T cells. These data demonstrate that Treg cells can play an important role in the regulation of immune responses of antigen-specific human memory γδ T cells.

During a variety of bacterial infections, γδ T cells have been found to expand to high levels, so that they represent the majority of circulating T cells in some individuals. Several lines of evidence suggest that γδ T cells contribute to the immune response to Mycobacterium tuberculosis. ESAT-6 is a very significant molecule in this subject, and we need to explore it more.