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We have previously identified a human CD8 HLA-DR regulatory T cell subset with the ability to suppress proliferation of autologous PBMCs responder cells through cell contact and CTLA-4 co-inhibitory molecule. The present study characterizes the complete phenotype of CD8 HLA-DR Treg cells which showed great similarities with classical CD4 cells expressing forkhead box P3 (FOXP3). The shared features included the expression of programmed cell death protein 1 (PD-1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), C-C chemokine receptor type 4 and 5 (CCR4 and CCR5), low expression of CD127, and a memory and effector-like phenotype. CD8 HLA-DR Treg-induced suppression on CD8 responder T cells was abrogated by an anti-PD1 neutralizing antibody. Anti-PD-1 did not abrogate the suppressor effect induced on responder CD4 T cells. In addition, CD8 HLA-DR Treg induced a preferential death on responder CD8 T cells. This effect was not reversed by PD-1 neutralization. After activation, most CD8 HLA-DR Treg acquire programmed death-ligand 1 (PD-L1) expression. Interestingly, PD-L1 may induce apoptosis through CD80 expressed on activated CD8 responder T cells. After PBMCs stimulation, CD8 HLA-DR Treg cells showed an increased frequency of IFN-γ and TNFα positive cells and higher degranulation. These data strongly argue against CD8 HLA-DR Treg being exhausted cells. Overall, the data presented in this study indicate that CD8 HLA-DR Treg and CD4 FOXP3 Treg share phenotypic and functional features, which may provide cues to similar involvements in the control of antitumor immune responses and autoimmunity.

Killer cell immunoglobulin-like receptor (KIR) genes are known to play a role in the acute phase of hepatitis C virus (HCV) infection. The present study investigated their roles in chronic HCV (CHCV) infection by analyzing the phenotypes and function of natural killer (NK) and T cells that express KIRs. T cells from CHCV patients showed a more differentiated phenotype, and NK cells exhibited an activated profile. These observations are consistent with the increased expression of the degranulation marker CD107a observed after PMA stimulation. We explored the correlations between the expression of KIR genes and lectin type-C receptors with clinical factors that predict progression to fibrosis and cirrhosis. The expression levels of KIR2DS3 and the functional alleles of KIR2DS4-FL were increased in patients with intermediate and high viral loads. Homozygous KIR2DS4 was also associated with the presence of cirrhosis. In the group of individuals with a shorter infection time who developed cirrhosis, we detected decreased expression of KIR3DL1 in CD56 NK cells in the presence of its ligand. Similarly, in the group of patients with late CHCV infections complicated with cirrhosis, we detected lower expression of the strong inhibitory receptor NKG2A in CD56 NK cells. We also detected an increase in NKG2C expression in CD56 NK cells in CHCV patients who displayed high necroinflammatory activity. Decreased KIR3DL2 expression in CD56 and CD56 NK cells was associated with a high body mass index, and KIR3DL2 expression may be one factor associated with the more rapid progression of CHCV to fibrosis in patients.

Human B‐cell studies in vitro have routinely used B lymphocytes purified from spleen, blood or tonsils irrespective of potential differences in their immunological traits. In this study, we compared the functional responses of total (CD19+) and memory B cells (Bmem; CD19+/CD27+) isolated from blood and tonsils to different stimuli. Peripheral B cells showed enhanced survival and proliferation compared with their tonsillar equivalents when stimulated for 10 days. Stimulated B cells from both tissues secreted significantly greater amounts of cytokines than unstimulated controls demonstrating their functional responsiveness. Analysis of CD27 expression over time indicated that the conditions that promoted survival and proliferation of peripheral Bmem, caused massive tonsillar Bmem death. Purified tonsillar Bmem failed to expand but rapidly differentiated in antibody secreting cells and subsequently underwent apoptosis. In contrast, circulating Bmem showed delayed activation and differentiation, but exhibited a longer lifespan and active proliferation. In addition, short‐term stimulation of tonsillar Bmem resulted in the production of more immunoglobulin G (IgG) than their peripheral counterparts. At later time points, however, IgG production from the different B cells was reversed. Our findings imply that the tissue located and peripheral Bmem have distinct behaviors, indicating organ dependent functional responses that should not be generalizable to all Bmem. This work provides a greater understanding of how Bmem location is coupled to specialized roles of B lymphocytes.

Active specific immunotherapy is a promising field in cancer research. N‐glycolyl (NGc) gangliosides, and particularly NGcGM3, have received attention as a privileged target for cancer therapy. Many clinical trials have been performed with the anti‐NGc‐containing gangliosides anti‐idiotype monoclonal antibody racotumomab (formerly known as 1E10) and the conjugated NGcGM3/VSSP vaccine for immunotherapy of melanoma, breast, and lung cancer. The present paper examines the role of NGc‐gangliosides in tumor biology as well as the available preclinical and clinical data on these vaccine products. A brief discussion on the relevance of prioritization of cancer antigens in vaccine development is also included.

Recently, it was shown that peripheral blood FOXP3+CD4+ T cells are composed of three phenotypic and functionally distinct subpopulations. Two of them having in vitro suppressive effects were characterized as resting Treg cells (rTregs) and activated Treg cells (aTregs). A third subset, identified as FOXP3+ non-Tregs, does not display any suppressor activity and produce high levels of Th1 and Th17 cytokines upon stimulation. In the present study we focus on the characteristics of these three subsets of FOXP3+CD4+ T cells in untreated HIV-1-infected patients. We found that the absolute counts of rTregs, aTregs and FOXP3+ non-Tregs were reduced in HIV-1 patients compared with healthy donors. The relative frequency of rTregs and aTregs was similar in HIV-1 patients and healthy donors, while the frequency of FOXP3+ non-Tregs was significantly higher in HIV-1 patients, reaching a maximum in those patients with the lower values of CD4 counts. Contrasting with the observations made in FOXP3- CD4+ T cells, we did not find a negative correlation between the number of rTregs, aTregs or FOXP3+ non-Tregs and virus load. Studies performed with either whole PBMCs or sorted aTregs and FOXP3+ non-Tregs cells showed that these two populations of FOXP3+ T cells were highly permissive to HIV-1 infection. Upon infection, FOXP3+ non-Tregs markedly down-regulates its capacity to produce Th1 and Th17 cytokines, however, they retain the ability to produce substantial amounts of Th2 cytokines. This suggests that FOXP3+ non-Tregs might contribute to the polarization of CD4+ T cells into a Th2 profile, predictive of a poor outcome of HIV-1-infected patients.

Adaptive NK cells constitute an NK cell subpopulation, which expands after human cytomegalovirus (HCMV) infection. This subpopulation has stronger production of cytokines after CD16 stimulation, longer life and persistence than conventional NK cells and are, therefore, interesting tools for cancer immunotherapy. Since there is limited information on adaptive NK cells in cancer patients, we described this population phenotypically and functionally, by flow cytometry, in the context of HER2 + breast cancer (BC) directed therapy. We assessed HCMV status in 78 patients with BC. We found that, similarly to healthy donors (HD), a high proportion of BC patients were HCMV-positive, and nearly 72% of them had an adaptive NK cell subpopulation characterized by the loss of FcεRIγ intracellular adaptor protein or the presence of NKG2C receptor. However, in BC patients, FcεRIγ−  and NKG2C + NK cell populations overlapped to a lesser extent than in HD. Otherwise, no profound phenotypic differences were found between BC patients and HD. Although FcεRIγ−  or NKG2C + NK cell subsets from BC patients produced more IFN-γ than their FcεRIγ + or NKG2C−  NK cell counterparts, IFN-γ production increased only when NK cells simultaneously expressed FcεRIγ− and NKG2C + , whereas in HD the presence of NKG2C marker was sufficient to display greater functionality. Furthermore, in a group of patients treated with chemotherapy and Trastuzumab plus Pertuzumab, FcεRIγ-NKG2C + and FcεRIγ-NKG2C− NK cells retained greater functionality after treatment than FcεRIγ + NKG2C−  NK cells. These results suggest that the presence or magnitude of adaptive NK cell subsets might serve as a key determinant for therapeutic approaches based on antibodies directed against tumor antigens.

Historical records suggest that Chiriguano tribe is the result of a genetic admixture event. The process involved the arrival of Guaraní tribesmen descending from Amazonian region of Brazil along with groups of Arawak origin that inhabited the foothill plains of Bolivia. Later they arrived in Argentina at the beginning of the twentieth century. Aiming to test the historical records, we analysed a set of 46 samples collected at San Ramon de la Nueva Orán, Province of Salta, Argentina. A wide set of uni- and biparentally transmitted genetic markers were analysed, including 23 autosomal STRs; 46 AIM-DIPs and 24 AIM-SNPs all located at diverse autosomal chromosome locations; 23 Y-STRs and the entire mtDNA D-Loop sequence. Ancestry informative markers allowed for the detection of a strong Native American component in the genomes (> 94%), while all mtDNA haplotypes showed Native American characteristic motives, and 93% of Y-haplotypes belonged to the Q1a3a Y-haplogroup. The analysis of mitochondrial haplotypes and Y chromosome, although they did not match other populations, revealed a relationship between the Chiriguano and other groups of Guaraní and Arawak origin inhabiting Brazil and Bolivia, confirming, at least in part, the historical records describing the origins of Chiriguano tribal settlements in northwestern Argentina.

The expression of N -glycolyl-monosialodihexosyl-ganglioside (NGcGM3) in humans is restricted to cancer cells; therefore, it is a tumor antigen. There are measurable quantities of circulating anti-NGcGM3 antibodies (aNGcGM3 Abs) in human serum. Interestingly, some people have circulating Ag-specific immunoglobulins G (IgGs) that are capable of complement mediated cytotoxicity against NGcGM3 positive cells, which is relevant for tumor surveillance. In light of the chemical nature of Ag, we postulated it as a candidate ligand for CD1d. Furthermore, we hypothesize that the immune mechanism involved in the generation of these Abs entails cross talk between B lymphocytes (Bc) and invariant natural killer T cells (iNKT). Combining cellular techniques, such as flow cytometry and biochemical assays, we demonstrated that CD1d binds to NGcGM3 and that human Bc present NGcGM3 in a CD1d context according to two alternative strategies. We also showed that paraformaldehyde treatment of cells expressing CD1d affects the presentation. Finally, by co-culturing primary human Bc with iNKT and measuring Ki-67 expression, we detected a reproducible increment in the proliferation of the iNKT population when Ag was on the medium. Our findings identify a novel, endogenous, human CD1d ligand, which is sufficiently competent to stimulate iNKT. We postulate that CD1d-restricted Bc presentation of NGcGM3 drives effective iNKT activation, an immunological mechanism that has not been previously described for humans, which may contribute to understanding aNGcGM3 occurrence.

Recent evidence has implicated galectins and their carbohydrate ligands as novel regulators of T-cell homeostasis. Galectin-1 (Gal-1), a member of this family, inhibits clonal expansion, induces apoptosis of antigen-primed T lymphocytes and suppresses the development of T-cell-mediated autoimmune diseases in vivo. Because the beta-galactoside-binding protein is expressed in activated but not resting T cells, it has been hypothesized that Gal-1-induced apoptosis may constitute an autocrine suicide mechanism to eliminate activated T cells contributing to the termination of an effector immune response. We undertook this study to investigate the signals and intracellular pathways leading to Gal-1 expression during T-cell activation. When T cells were stimulated either with anti-CD3 or anti-CD28 monoclonal antibody plus PMA in the presence of accessory cells, a sustained up-regulation of Gal-1 was observed, reaching a plateau between days 3 and 5 following CD3 engagement or costimulation through CD28. Investigation of the signal transduction events involved in this process revealed a role for Lck and Fyn kinases, since the Src kinase inhibitor PP1 inhibited the up-regulated expression of Gal-1 following T-cell activation. Downstream signaling routes involve mitogen-activated protein kinase (MAPK) kinase (MEK)1/extracellular signal-regulated kinase (ERK) and p38 MAPK, as Gal-1 expression was prevented by U0126 and SB202190. In addition, expression of Gal-1 involves interleukin (IL)-2-dependent signaling routes triggered by p70S6 kinase, as it could be inhibited by rapamycin. This is the first demonstration of the intracellular pathways that control activation-induced expression of Gal-1, which may reveal potential targets for immune intervention to modulate expression of this beta-galactoside-binding protein in pathological disorders.