Response: Human memory but not naïve γδ T cells from TST-positive individuals respond to M tuberculosis antigen

We thank Casetti et al for their interest in our recent work, “CD4⁺CD25⁺ Treg cells inhibit human memory γδ T cells to produce IFN-γ in response to M tuberculosis antigen ESAT-6.”¹  In our article, we showed that stimulation of peripheral blood mononuclear cells (PBMCs) from tuberculin skin test (TST)–positive individuals with ESAT-6 resulted in not only the production of cytokines but also the activation and division of memory γδ T cells. These responding γδ T cells displayed the phenotype of memory but not naive γδ T cells. Most interestingly, CD4⁺CD25⁺ Treg cells could inhibit IFN-γ production by γδ T cells.

Casetti et al observed that CD4⁺ but not γδ T cells from 4 patients with active tuberculosis (TB) disease and 4 subjects with latent TB infection (LTBI) responded to ESAT-6 to express IFN-γ. In accordance with their and others' observations,²  in our unpublished data from a few active TB patients, we also found that CD4⁺ T cells, in addition to γδ T cells, produced IFN-γ in response to ESAT-6. Of note, the cells from different individuals with TB infection had distinct quality of response. The discrepancies between their and our results on the response of γδ T cells to ESAT-6 might be influenced by many factors. The concern might be that the source of ESAT-6 we purchased from suppliers was different from that Casetti et al used. The various preparations of recombinant antigens, including cloning, sequences, expression, and purification process from different companies, might have different biologic activities. Moreover, differences in the classical and nonclassical major histocompatibility class (MHC) molecules, the affinity to antigenic epitopes, and the distinct biologic features between eastern and western peoples might lead to distinct reactivity to the same antigen. Clearly, it has been reported that γδ T cells from bovines could react to ESAT-6 by IFN-γ production and proliferation.³  In addition, several antigenic epitopes/proteins recognized by human γδ T cells have been identified via CDR3δ peptide–based immunobiochemical strategy.⁴  These peptides not only bind to γδ T cells but also activate γδ T cells. Moreover, in human chronic human herpesvirus 8 (HHV-8) infection, purified viral proteins resulted in γδ Vδ1 T cell activation.⁵  Taken together, we agree with Casetti et al that human γδ T cells recognize nonpeptidic phosphoantigens, metabolites of the isoprenoid pathway.^6,7  However, the mechanism by which human γδ T cells recognized protein antigens remains unclear currently and needs further investigation.