Six-of-the-best: unique contributions of γδ T cells to immunology

Abstract

γδ T cells are a unique and conserved population of lymphocytes that have been the subject of a recent explosion of interest owing to their essential contributions to many types of immune response and immunopathology. But what does the integration of recent and long-established studies really tell us about these cells and their place in immunology? The time is ripe to consider the evidence for their unique and crucial functions. We conclude that whereas B cells and αβ T cells are commonly thought to contribute primarily to the antigen-specific effector and memory phases of immunity, γδ T cells are distinct in that they combine conventional adaptive features (inherent in their T cell receptors and pleiotropic effector functions) with rapid, innate-like responses that can place them in the initiation phase of immune reactions. This underpins a revised perspective on lymphocyte biology and the regulation of immunogenicity.

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

“…Vc9/Vd2 T cells and other unconventional T cells in humans and in mice clearly regulate a plethora of distinct immune responses, by interacting with local immune and non-immune cells, and may thereby influence homeostatic, anti-microbial, anti-tumor and tissue repair responses [1][2][3][4][5][6][7]. It is conspicuous that the generation and maturation of effective APCs appears to be a common endpoint of Vc9/Vd2 T cell-triggered interactions with neutrophils, monocytes and immature DCs as well as B cells, in combination with the unexpected potential of Vc9/Vd2 T cells themselves to act as professional APCs (Fig.…”

“…30 years have passed since the accidental and unexpected cloning of the cd T cell receptor (TCR) and the subsequent realization that ab T cells and cd T cells are fundamentally different with respect to the types of antigens they recognize and the distinct effector functions triggered upon such recognition. However, the manifold contributions of cd T cells to homeostasis, inflammation, infection and tumor surveillance have historically been neglected and are only beginning to be integrated into comprehensive models of the immune system [1][2][3][4][5][6][7].…”

“…cd T cells represent a third lineage of lymphocytes expressing re-arranged antigen receptors that co-evolved with 'classical' B cells and ab T cells over 400 million years, arguing for a crucial and non-redundant contribution of each lymphocyte to effective immune responses, and hence the evolutionary survival of all jawed vertebrate species [1]. 30 years have passed since the accidental and unexpected cloning of the cd T cell receptor (TCR) and the subsequent realization that ab T cells and cd T cells are fundamentally different with respect to the types of antigens they recognize and the distinct effector functions triggered upon such recognition.…”

“…This intracellular recognition of HMB-PP and IPP evokes similar cases of B30.2-mediated innate responses through proteins such as TRIM5a and TRIM21 [26,27], thereby adding BTN3A to the rapidly growing number of innate pattern recognition receptors. Despite this progress, the precise mechanism of how the HMB-PP/BTN3A complex might engage the TCR of Vc9/Vd2 T cells awaits further elucidation.Once activated, Vc9/Vd2 T cells exert a range of different effector functions by killing infected and stressed target cells, driving inflammatory and wound healing processes, promoting survival of monocytes and neutrophils, inducing maturation of dendritic cells (DCs), providing B cell help, and priming CD4 + and CD8 + T cells [1][2][3][4][5][6][7]. In the following chapters we will review findings showing that Vc9/Vd2 T cells, and possibly other unconventional human T cells, play an important role in bridging innate and adaptive immunity by promoting the activation and differentiation of various types of antigen-presenting cells (APCs) and even turning into APCs themselves, and thereby pave the way for antigen-specific effector responses and long-term immunological memory (Fig.…”

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

“…However, the context of IPP recognition by the Vg9Vd2 TCR remains elusive. The Ag-presenting element awaits identification, and accessory cell requirements of gd T cell activation are still poorly defined (19). Although monocytes were postulated to be required as a source of IPP in zoledronate-induced gd T cell responses (20), primary human MHC class II + cells were recently reported to be indispensable for gd T cell expansion in response to stimulation with phosphoantigens (21).…”