Human Peripheral Blood Gamma Delta T Cells: Report on a Series of Healthy Caucasian Portuguese Adults and Comprehensive Review of the Literature

Abstract

Gamma delta T cells (Tc) are divided according to the type of Vδ and Vγ chains they express, with two major γδ Tc subsets being recognized in humans: Vδ2Vγ9 and Vδ1. Despite many studies in pathological conditions, only a few have quantified the γδ Tc subsets in healthy adults, and a comprehensive review of the factors influencing its representation in the blood is missing. Here we quantified the total γδ Tc and the Vδ2/Vγ9 and Vδ1 Tc subsets in the blood from 30 healthy, Caucasian, Portuguese adults, we characterized their immunophenotype by 8-color flow cytometry, focusing in a few relevant Tc markers (CD3/TCR-γδ, CD5, CD8), and costimulatory (CD28), cytotoxic (CD16) and adhesion (CD56) molecules, and we examined the impacts of age and gender. Additionally, we reviewed the literature on the influences of race/ethnicity, age, gender, special periods of life, past infections, diet, medications and concomitant diseases on γδ Tc and their subsets. Given the multitude of factors influencing the γδ Tc repertoire and immunophenotype and the high variation observed, caution should be taken in interpreting "abnormal" γδ Tc values and repertoire deviations, and the clinical significance of small populations of "phenotypically abnormal" γδ Tc in the blood.Cells 2020, 9, 729 2 of 40 associates with Vγ9 in most cases, defining a Vγ9Vδ2 Tc population that is unique to humans and other primates, whereas Vδ1 Tc use diverse Vγ regions [4][5][6].Gamma delta Tc is involved in the immune response to viruses, intracellular bacteria, and parasitic protozoa [7][8][9][10][11][12][13][14]; is involved in immune surveillance against hematological neoplasms and solid tumors [15][16][17] and the pathogenesis of autoimmune diseases [18,19]; and abnormal percentages and/or absolute numbers of γδ Tc involving different γδ Tc subsets have been reported in the PB and in different organs from patients with various pathological conditions. Vδ2 Tc respond mainly to intracellular bacteria and solid tumors, while Vδ1 Tc, resident mainly in tissues, is used mostly in the defense against viruses and malignancies, although this dichotomy is not absolute. In addition, γδ T-cells are being explored in cell-based immunotherapy [20][21][22].In parallel to the low frequency of γδ Tc, lymphoproliferative disorders (LPD) of γδ Tc are rare disease conditions. These comprise γδ Tc large granular lymphocyte (LGL) proliferations, including γδ Tc LGL leukemia, defined as clonal expansions of cytotoxic γδ Tc, which have an indolent clinical course and often coexist with cytopenias and other pathologies [23,24], and hepatosplenic and other γδ Tc lymphomas, which usually have an aggressive clinical course, poor response to chemotherapy and short survival [25][26][27][28].Gamma delta Tc expressing Vγ9Vδ2 are known to identify microbe-derived (e.g., (E)-4-hydroxy-3methyl-but-2-enyl pyrophosphate, HMB-PP) and host-derived (e.g., isopentenyl pyrophosphate, IPP) phosphorylated metabolites ("phosphoantigens") originating from the isoprenoid metabolic mevalonate and non-me...

Translating Unconventional T Cells and Their Roles in Leukemia Antitumor Immunity

“…Once activated, these lymphocytes secrete effector molecules such as IFN- γ , TNF, perforins, and granzymes and exert important cytotoxic activities in peripheral blood against pathogens and tumors [ 12 , 61 ]. These cells make up as much as 95% of blood γδ T cells [ 50 , 62 – 64 ] and generally respond to a wide variety of pAgs, such as IPP (isopentenyl pyrophosphate) and HMB-PP (4-hydroxy-3-methyl-but-2-enylpyrophosphate), which are intermediates of the mevalonate pathway in eukaryotes and prokaryotes [ 65 – 67 ]. The recognition of these pAgs occurs in the context of the butyrophilin (BTN) family of molecules, such as BTN3A1 and BTN2A1 [ 68 – 71 ], which can be detected in LCs, and mediates a potent immune response that can be used therapeutically [ 72 ].…”

The Roles of γδ T Cells in Hematopoietic Stem Cell Transplantation

“…Based on the difference of T cell receptor (TCR), T cells can be divided into αβ T cells and γδ T cells. A large amount of T cells are αβ T cells, while γδ T cells account for a small proportion, approximately 1.2%–15.4% 13 . Human γδ T cells can be recognized by the expression of TCR Vδ and TCR Vγ, and TCR Vδ1, Vδ2, Vδ3, Vγ2, Vγ3, Vγ4, Vγ5, Vγ8, Vγ9, and Vγ11 are the most commonly used gene fragments for rearrangement of δ and γ chains 14 .…”

“…And γδ T cells can induce the antitumor cytotoxicity of other cells, especially natural killer (NK) cells 28 . Additionally, subsets of γδ T cells coexpress some receptors of NK cells like natural killer group 2D (NKG2D), DNAM-1, and CD16 13 , 29 , 30 . Moreover, NKG2D that is expressed on Vδ1 T cells can be combined with MHC class I chain-related A (MICA), and this combination between MICA and NKG2D was stronger than the one between MICA and TCR 31 .…”

Quantification of Immune Variables from Liquid Biopsy in Breast Cancer Patients Links Vδ2+ γδ T Cell Alterations with Lymph Node Invasion

“…Still, upon antigenic stimulation, CM γδ T cells can further mature to CD45RA − CCR7 − CD27 + / − CD28 + / − effector memory (EM) γδ T cells, producing pro-inflammatory cytokines (IFN-γ, TNF-α) and cytolytic protein (granzymes, perforin). EM γδ T cells finally mature to CD45RA + CCR7 − CD27 − CD28 − re-expressing CD45RA terminally differentiated effector memory (TEMRA) γδ T cells with low proliferative potential and strong cytotoxic function [ 30 , 31 , 32 ]. While losing the expression to markers associated with immature γδ T cells profiles (e.g., IL7R), the latter express CD16, being able to mediate antibody-dependent cell cytotoxicity (ADCC), and can express CD57, a canonical marker of cellular aging and replicative senescence, also associated with impaired cytotoxic functionality.…”