Natural and synthetic non-peptide antigens recognized by human γδ T cells

Abstract

T lymphocytes express either alpha beta or gamma delta T-cell receptor heterodimers. Most alpha beta T cells recognize antigenic peptides bound to major histocompatibility complex molecules but the antigen recognition and biological function of gamma delta T cells is unknown. A major human gamma delta T-cell subset expressing V gamma 2 and V delta 2 germline genes, but having diverse junctional sequences, is found in human mycobacterial lesions and responds in vitro to antigens of bacteria and parasites. In addition, certain haematopoietic tumour cells are specifically recognized and lysed by these T cells. V gamma 2V delta 2-bearing T cells were shown to recognize mycobacterial antigens that are protease resistant and phosphatase sensitive. Because of the difficulty in isolating natural antigens from mycobacterial culture filtrates or extracts, we synthesized a series of monoalkyl phosphates, and found that some, particularly monoethyl phosphate, could mimic the activity of mycobacterial antigens in stimulating these gamma delta T cells. Here we report the identification of natural antigens produced by mycobacteria recognized by human V gamma 2V delta 2-bearing T cells as isopentenyl pyrophosphate and related prenyl pyrophosphate derivatives, compounds involved in the synthesis of complex polyisoprenoid compounds in microbial and mammalian cells. Substitution of phosphate for the pyrophosphate moiety, or elimination of the double bond, greatly reduced antigenic activity of these compounds. These results provide formal evidence that, in contrast to recognition of major histocompatibility complex-bound peptide antigens by alpha beta T cells, human gamma delta T cells can recognize naturally occurring small non-peptidic antigens.

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

“…6 Endogenously, IPP and its stereoisomer dimethylallyl diphosphate are substrates produced in the mevalonate pathway for cholesterol metabolism; however, they can also be produced by the deoxyxylulose pathway commonly used by organisms, such as Escherichia coli and certain plant cells, that lack the critical HMGCoA reductase enzyme of the mevalonate pathway. 65,66 It was later determined that the stimulatory capacity of IPP and dimethylallyl diphosphate is actually fairly weak in comparison to some of the upstream intermediates of the alternative pathway of isoprenoid biosynthesis, such as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate, 67 and it is usually in the context of malignancy or distress that cellular endogenous levels are able to awaken the effector functions of Vc9Vd2 T cells. 68 A class of drugs called aminobisphosphonates used for the prevention of bone fragility fractures and certain alkylamine compounds that are ubiquitously dispersed in everything from plants to amniotic fluid are also able to stimulate Vc9Vd2 T cells 69,70 by virtue of their ability to induce cellular accumulation of IPP.…”

Dendritic cells cross-talk with tumour antigen-specific CD8+ T cells, Vγ9γδT cells and Vα24NKT cells in patients with glioblastoma multiforme and in healthy donors

“…They subsequently induce tumour antigen‐specific CD8 + T cells in vivo in which Vα24NKT cells may function as helper T cells producing large amounts of IFN‐γ, as shown in our previous clinical study 4. Note that the concurrent activation and proliferation of Vγ9γδT cells by Z is MHC‐unrestricted 43 and that Vα24NKT cells recognize G presented by non‐polymorphic CD1d molecules 3. Therefore, the adjuvant effect of the combination of Z and G is theoretically applicable to all cancer patients.…”

Mucosal lymphatic-derived γδ T cells respond early to experimental Salmonella enterocolitis by increasing expression of IL-2Rα

“…This response is similar, in part, to an antigen driven response, except it occurs with a large fraction of the naive γδ T cell population. Also, though it is widely accepted that γδ T cells recognize microbial nonpeptidic phosphorylated molecules [16][17][18] and alkylamines [19,20] in a TCRdependent manner, LPS has not, to our knowledge, been described as a TCR ligand. While we have not precisely determined the mechanism of LPS detection, transcripts encoding many TLRs and other pattern recognition proteins are readily detected in γδ T cells [15,[21][22][23][24][25].…”