Molecules and Mechanisms Implicated in the Peculiar Antigenic Activation Process of Human Vγ9Vδ2 T Cells

Abstract

In human beings, as well as in most non-human primates, the major peripheral γδ T cell subset, which accounts several percent of the whole lymphoid cells pool in adults, carries an heterodimeric TCR composed of Vγ9 and Vδ2 chains. Vγ9Vδ2 T cells are specifically and strongly activated by small organic pyrophosphate molecules termed phosphoantigens (phosphoAg). These low molecular weight compounds are metabolites that are produced by either microbes or endogenously, as intermediates of the mammalian mevalonate pathway, and can accumulate intracellularly during cell stress like transformation or infection. Despite the characterization of numerous natural and synthetic phosphoAg, the mechanism(s) underlying the unique and specific antigenic activation process induced by these compounds remains poorly understood. Activation is both TCR- and cell-to-cell contact-dependent, and results of previous studies have also strongly suggested a key contribution of membrane-associated molecules of primate origin expressed on target cells. The recent identification of B7-related butyrophilin (BTN) molecules CD277/BTN3A, and more precisely their BTN3A1 isoforms, as mandatory molecules in the phosphoAg-induced recognition of target cells by Vγ9Vδ2 T cells opens important opportunities for research and applications in this field. Here, we review the unusual and complex antigenic reactivity of human Vγ9Vδ2 T cells. We highlight the recent advances in our understanding of this process, and propose a model that integrates the type I glycoprotein BTN3A1 and its intracellular B30.2 domain as a physical intermediate implicated in the detection of dysregulated intracellular levels of phosphoAg and the sensing of cell stress by Vγ9Vδ2T cells. A better understanding of this mechanism will help optimize novel immunotherapeutical approaches that utilize the unique functional potential of this major γδ T cell subset.

Keywords: antigenic activation; butyrophilin; functions; human γδ T lymphocytes; phosphoantigens.

Figure 1

Examples of characterized phosphoantigens that induce Vγ9Vδ2 T cell activation. These listed phosphoAg are either from natural or synthetic origin. They induce different range of activation with EC₅₀ value for Vγ9Vδ2 T cell activation that can vary between different human donors. From Ref. (64, 36, 39, 97).

Figure 2

Three hypothetical activation mechanisms for the induction of human Vγ9Vδ2 T cells activation by phosphoantigens. (A) Hypothesis #1: phosphoAg are produced intracellularly or internalized by unidentified membrane transporter(s). They interact with the intracellular B30.2 domain of BTN3A1, which induces non-exclusive key modifications such as conformational changes of the protein, modifications of its membrane topology, recruitment/exclusion of molecular partners. These modifications are then sensed by Vγ9Vδ2 T cells, leading to their functional activation. (B) Hypothesis #2: Intracellular phosphoAg are exported from the cell by unidentified membrane transporter(s). Both extra- and intracellular phosphoAg interact with the extracellular part of CD277/BTN3A. phosphoAg are presented by the extracellular IgV domain, as antigenic complexes to the Vγ9Vδ2 TCR, which leads to γδ T cell functional activation. (C) Hypothesis #3: this model shares mechanisms from both hypothesis #1 and #2 models. Intracellular phosphoAg interact with the intracellular B30.2 domain of BTN3A1. They are then exported from the cell by BTN3A1 itself, or a membrane transporter(s) associated with BTN3A1. Both extra- and intracellular phosphoAg can then interact with the extracellular IgV domain of BTN3A1 and trigger Vγ9Vδ2 T cell activation.

Figure 3

Different steps of the activation process of human Vγ9Vδ2 T cells induced by phosphoantigens. All the steps/molecules colored in red have been identified while the green ones will need to be confirmed. PhosphoAg (pAgs) accumulate intracellularly as metabolites of the endogenous mevalonate pathway (MVA) or the microorganism MEP/DOXP pathway. Exogenous pAg can also be internalized through yet undefined membrane transporter(s). PhosphoAg directly interact with the N-terminal portion of the intracellular B30.2 domain of CD277/BNT3A1. Intracellular partner molecules could be recruited either by BTN3A1 or by phosphoAg. Following PhosphoAg/B30.2 interaction, the conformation of BTN3A1 is altered and the cell surface distribution of BTN3A1 together with yet unknown other molecular partners is modified. These exquisite signals are sensed by Vγ9Vδ2 T cells, in a TCR-dependent manner, leading to the functional activation of γδ T cells. Whether the Vγ9Vδ2 TCR directly interacts with BTN3A1 remains unclear.