Studies of chemokine receptors (CKR) in natural killer- (NK-) cells have already been published, but only a few gave detailed information on its differential expression on blood NK-cell subsets. We report on the expression of the inflammatory and homeostatic CKR on normal blood CD56+low CD16+ and CD56+high  CD16−/+low NK-cells. Conventional CD56+low and CD56+high NK-cells present in the normal PB do express CKR for inflammatory cytokines, although with different patterns CD56+low NK-cells are mainly CXCR1/CXCR2+ and CXCR3/CCR5−/+, whereas mostly CD56+high NK-cells are CXCR1/CXCR2− and CXCR3/CCR5+. Both NK-cell subsets have variable CXCR4 expression and are CCR4− and CCR6−. The CKR repertoire of the CD56+low NK-cells approaches to that of neutrophils, whereas the CKR repertoire of the CD56+high NK-cells mimics that of Th1+ T cells, suggesting that these cells are prepared to migrate into inflamed tissues at different phases of the immune response. In addition, we describe a subpopulation of NK-cells with intermediate levels of CD56 expression, which we named CD56+int NK-cells. These NK-cells are CXCR3/CCR5+, they have intermediate levels of expression of CD16, CD62L, CD94, and CD122, and they are CD57− and CD158a−. In view of their phenotypic features, we hypothesize that they correspond to a transitional stage, between the well-known CD56+high and CD56+low NK-cells populations.

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...

We report 12 cases of aggressive natural killer (NK) cell neoplasms diagnosed in Portugal, with emphasis on flow cytometry. Ten patients had extranodal NK/T cell lymphoma, nasal type and two had aggressive NK cell leukemia, and seven were men and five were women, with a median age of 50 years. NK cells brightly expressed the CD56 adhesion molecule and CD94 lectin type killer receptor and had an activation-related HLA-DR+ CD45RA+ CD45RO+ immunophenotype, in most cases. In contrast, dim CD16 expression was found in a minor proportion of cases, whereas CD57 and the CD158a and CD158e1 killer immunoglobulin-like receptors were negative. One-third of cases showed a hyperploid DNA content and nearly all had a very high S-phase proliferative rate. The phenotypic features of the neoplastic NK cells would suggest that they represent the transformed counterpart of the CD56 + bright NK cells that circulate in normal blood.